Nickel-Catalyzed Amination of (Hetero)aryl Halides Facilitated by a Catalytic Pyridinium Additive

Article abstract of DOI:10.1002/chem.202002800

An efficient and operationally simple Ni-catalyzed amination protocol has been developed. This methodology features a simple Ni^II salt, an organic base and catalytic amounts of both a pyridinium additive and Zn metal. A diverse number of (hetero)aryl halides were coupled successfully with primary and secondary alkyl amines, and anilines in good to excellent yields. Similarly, benzophenone imine gave the corresponding N-arylation product in an excellent yield.

Full text of DOI:10.1002/chem.202002800

Accepted Article
Accepted Article
Title: Nickel-Catalyzed Amination of (Hetero)aryl Halides Facilitated by
a Catalytic Pyridinium Additive
Authors: Dongyang Han, Sasa Li, Siqi Xia, Mincong Su, and Jian Jin
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202002800
Link to VoR: https://doi.org/10.1002/chem.202002800
01/2020

10.1002/chem.202002800
Chemistry - A European Journal
COMMUNICATION
Nickel-Catalyzed Amination of (Hetero)aryl Halides Facilitated by
a Catalytic Pyridinium Additive
Dongyang Han,[a,†] Sasa Li,[a,†] Siqi Xia,[b] Mincong Su,[b] and Jian Jin*[a]
Dedicated to the 70th anniversary of Shanghai Institute of Organic Chemistry
[a]
D. Han, S. Li, Prof. Dr. J. Jin
CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis
Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032, China
E-mail: jjin@sioc.ac.cn
[b]
[†]
S. Xia, M. Su
Center for Supramolecular Chemistry and Catalysis and Department of Chemistry, College of Sciences
Shanghai University
99 Shangda Road, Shanghai 200444, China
These authors contributed equally.
Supporting information for this article is given via a link at the end of the document.
Abstract: An efficient and operationally simple Ni-catalyzed
amination protocol has been developed. This methodology features a
simple Ni(II) salt, an organic base and catalytic amounts of both a
pyridinium additive and Zn metal. A diverse number of (hetero)aryl
halides were coupled successfully with primary and secondary alkyl
amines, and anilines in good to excellent yields. Similarly,
benzophenone imine gave the corresponding N-arylation product in
an excellent yield.
amination and Cu-catalyzed Ullmann–Ma coupling, Ni-catalyzed
amination is still not that attractive for industrial applications.
Ar
rate-limiting ligand modulation
Ni0
LnNiII NR1R2
slow
fast
I
NR1R2
Ar
Ar
photoredox catalysis
electrochemistry
LnNiIII NR1R2
fast
X
II
Aryl amines are the widespread constituents of natural products
and pharmaceutical compounds, which render the amination
reaction one of the most frequently employed reactions in
medicinal chemistry.[1] Over the past 25 years, the Pd-catalyzed
cross-coupling of amines with aryl halides or pseudohalides,
named Buchwald–Hartwig amination has evolved into a powerful
tool for the C(sp2)–N bond formation through development of the
multiple generations of ligands, typically phosphines.[2] Similarly,
the Cu-catalyzed Ullmann–Ma coupling has been elevated to an
essential transformation by the introduction of diverse nitrogen
ligands, such as diamines, amino acids, and oxalic diamides.[3] In
recent years, we have observed an ongoing renaissance in nickel
catalysis.[4] In fact, the first Ni-catalyzed C–N coupling using NiCl2
at 200 °C dates back to 1950.[5] The seminal contributions from
Buchwald, Lipshutz, Chatani, Garg, Hartwig, Montgomery and
others have significantly improved Ni-catalyzed amination with
Ni(0) catalysts and Ni(II) pre-catalysts.[6,7] It was believed that
most of those Ni-catalyzed amination systems involved the Ni(II)
amido complexes I, followed by the rate-limiting C–N reductive
elimination (Figure 1).[8] Stradiotto and co-workers provided an
elegant solution to promote Ni-catalyzed C–N coupling by tailored
ancillary ligand design.[9] In 2016, MacMillan and Buchwald
this work
NiI (NiII + Zn)
pyridinium additive
+ e
organic base
R
R
N
N
Me
Me
− e
additive
electron shuttle
III
Figure 1. Design Plan for the Nickel-Catalyzed Amination.
We envisioned an operationally simple approach to establish a
Ni(I)/Ni(III) catalytic cycle starting from a Ni(II) precursor by in situ
reduction to Ni(I) species with heterogeneous Zn metal.[13] The
latter then would undergo oxidative addition with an aryl halide
followed by halide-amide exchange to give the Ni(III) amido
complex II (Figure 1).[14] Amination reactions catalyzed by Pd, Cu,
and Ni traditionally employed inorganic bases, such as NaOt-Bu
and K3PO4. There is an increasing interest in the use of soluble
organic bases for the cross-coupling.[15] We were interesting in
finding an efficient organic base for our Ni-catalyzed amination
system. More importantly, we took a different strategy from the
prior efforts which were devoted to ligand and precatalyst design
to enhance the efficacy of Ni-catalyzed C–N coupling. We
assumed that an organic additive would act as an electron shuttle
developed
a distinct photoredox protocol to address the
challenging reductive elimination issue via the intermediacy of a
Ni(III) amido complex II.[10] Since then, a variety of photoinduced
amination reactions have been reported.[11] Very recently, Baran
successfully realized a complementary electrochemical strategy
to precisely control the redox states in Ni-catalyzed amination.[12]
However, as compared to Pd-catalyzed Buchwald–Hartwig
1
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1 mol% (dppp)NiCl2
(Figure 1, bottom) to facilitate the inter-transformation of different
Ni species, such as in situ reduction of Ni(II) to Ni(I) under
heterogeneous conditions. It was noticed that pyridinium salts had
1 mol% dtbbpy
15 mol% Zn
Br
N
N
H
red
been widely explored as electron mediators.[16] And the E1/2
MeO2S
5 mol% additive 1
1.5 equiv. t-BuTMG
2 mL DMSO, 60 ℃, 2 h
MeO2S
[16a]
values of pyridiniums
should be comparable to that of
1.5 equiv.
99% yield
0.5 mmol
Ni2+/Ni+.[12b] We report here on our preliminary results of Ni-
catalyzed amination of (hetero)aryl halides facilitated by catalytic
amount of a pyridinium additive.
C−N product 1
entry
yield [%]
variation from standard conditions
As part of our long-term interest in heteroatom-heteroatom and
carbon-heteroatom bond formation,[17] we started our exploration
into Ni-catalyzed amination of aryl halides (Table 1). 4-
Bromophenyl methyl sulfone and pyrrolidine were chosen as the
model substrates. To our delight, after extensive evaluation of
various reaction parameters, the desired C–N coupling product 1
was obtained in 99% yield with 1 mol% of (dppp)NiCl2/dtbbpy as
the precatalyst, 15 mol% of zinc metal as the Ni(II) reductant, 5
mol% of 1-methyl-4-phenylpyridinium iodide as the additive, and
t-BuTMG as the organic base. The essential roles of nickel salt,
bipyridine ligand, Zn metal, organic base, and additive were firstly
demonstrated by the control experiments (entries 1–5). Without
any one of these reagents, it led to 0 to 7% yields of the amination
product. The other common Ni(II) salts afforded similar catalytic
efficiency with slightly decreased yields (entries 6–8). It is worth
mentioning that NiCl2·6H2O performed well for the amination
protocol, implying that a phosphine ligand is not required. The
Ni(0) complex exhibited similar catalytic efficacy with Ni(II)
precatalysts under otherwise the same conditions. However, it
lost the catalytic ability without Zn metal and additive 1,
suggesting that Ni(0) might not be the productive catalyst (entries
9 and 10). Notably, replacement of dtbbpy with dphbpy and even
the parent bipyridine ligand bpy could maintain the high yields
(entries 11 and 12). Although Mn metal only furnished the product
1 in 29% yield after 2 h (entry 13), in some cases superiority of
Mn to Zn could be observed (vide infra). Experiments were also
carried out to replace 1-methyl-4-phenylpyridinium iodide by other
pyridinium salts (entries 14–17). The pyridinium additives 2 and 3
with the C2-phenyl and C4-methyl groups, respectively, provided
the amination product in 78-87% yields, while the pyridium
additive 4 and 5 only afforded 51% and 18% of the amination
product, respectively. Moreover, 4-phenylpyridine, n-Bu4NI and KI
almost had no impact on the reaction, demonstrating that the
pyridinium moiety was critical for the promoting effect (entries 18–
20). It was noted that the amination could proceed successfully in
DMF and NMP, although not efficiently in MeCN, under the
standard conditions (entries 21–23). Other transition metals were
ruled out by the control experiments (entry 24). No product was
formed when CrCl3, FeCl2, MnCl2, CoCl2, CuCl2, or PdCl2 was
used under otherwise the same conditions. Finally, a number of
common organic bases, such as Et3N, i-Pr2NEt, DABCO and DBU
were screened for the amination reaction, but <10% yields of the
product 1 were observed.
1
no nickel salt
no bipyridine ligand
0
2
3
3
no Zn
4
4
no additive 1
7
5
no t-BuTMG
7
6
NiCl2Ƅ6H2O instead of (dppp)NiCl2
(glyme)NiCl2 instead of (dppp)NiCl2
(dppe)NiCl2 instead of (dppp)NiCl2
Ni(cod)2 instead of (dppp)NiCl2
91
93
94
91
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Ni(cod)2 instead of (dppp)NiCl2, no Zn, no additive 1
dphbpy instead of dtbbpy
7
97
94
29
78
87
51
18
6
bpy instead of dtbbpy
Mn instead of Zn
additive 2 instead of additive 1
additive 3 instead of additive 1
additive 4 instead of additive 1
additive 5 instead of additive 1
4-phenylpyridine instead of additive 1
n-Bu4NI instead of additive 1
KI instead of additive 1
5
6
DMF instead of DMSO
94
90
54
0
NMP instead of DMSO
MeCN instead of DMSO
Cr, Fe, Mn, Co, Cu or Pd salt instead of Ni salt
Et3N, i-Pr2NEt, DABCO, DBU instead of t-BuTMG
<10
PPh2
OMe
Ph2P
PPh2
Ph2P
MeO
dppp
dppe
glyme
t-Bu
t-Bu
Ph
Ph
N
N
N
N
N
N
dtbbpy
dphbpy
bpy
N
t-Bu
N
I
Ph
I
Me
Me
Me
N
N
Me
N
Me
Me
Me
Ph
t-BuTMG
additive 1
additive 2
MeO2C
I
I
I
N
N
N
Me
Me
Me
additive 3
additive 4
additive 5
[a] Yields determined by 1H NMR using 1,3-benzodioxole as an internal
standard in CDCl3.
Encouraged by the preliminary results, we sought to evaluate
the generality of this nickel-catalyzed amination protocol. The
scope of (hetero)aryl electrophiles was examined using
pyrrolidine as the amine coupling partner, that is the most
common five-membered heterocycle in medicines.[18] For every
substrate in this work, two sets of reactions were performed with
and without the additive 1. As illustrated in Scheme 1, the catalytic
amount of additive 1 could have an impressive promoting effect
for most of the substrates. A wide range of (hetero)aryl bromides
Table 1. Optimization for the Nickel-Catalyzed Amination[a].
2
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and chlorides were found to be competent coupling partner for the
reaction. Electron-poor aryl bromides reacted readily to form the
amination products in high yields (1–7) while electron-rich aryl
halides gave very poor yields of <20% (data not shown). The 4-
nitrophenyl bromide (5) and 2-cyanophenyl bromide (7) exerted a
diminished additive effect. We speculated that the strong
electron-withdrawing effect of para-nitro and ortho-CN groups
rendered these substrates already highly reactive. A variety of six-
membered heteroaromatic halides performed well under the
reaction conditions to furnish the heteroaryl amines of medicinal
relevance. The halogen derivatives of quinoline (8–10),
isoquinoline (11 and 12), quinoxaline (13 and 14), quinazoline
(15–17), pyridine (18–21), pyrazine (22), and pyrimidine (23–27)
were successfully coupled with pyrrolidine, demonstrating the
high functional group tolerance of this method. Moreover, five-
membered heteroaromatic halides were also amenable to this
reaction, including but not limited to benzoxazole (28),
benzothiazole (29), and thiazole (30). Remarkedly, sulfur-based
functional groups were compatible with the Ni-catalyzed system
(27, 29 and 30).
Next, the scope of amine nucleophiles was explored to gain
further insight into the capability of pyridinium-facilitated
amination (Scheme 2). Generally, the conversion of secondary
alkyl amines to the corresponding C–N coupling products was
dramatically improved in the presence of additive 1. A series of
cyclic secondary amines with different ring sizes provided good to
excellent yields of the desired amination products. A broad variety
of functional groups on the amine substrates were feasible, such
as Boc (35 and 54) and acetal (45) protecting groups, morpholinyl
(42), difluoromethylene (46), alkenyl (52), and pyridinyl (53)
groups. The C–N coupling reaction showed excellent chemo- and
regio-selectivity. For instance, the amine was arylated smoothly
leaving the hydroxy group untouched (43). Also, the arylation
preferentially occurred at the less sterically congested site for 2-
methylpiperazine (48). It is of note that acyclic secondary amines
worked as well in this C–N coupling reaction (57–60).
1−5 mol% (dppp)NiCl2
1−5 mol% dtbbpy
X
N
15 mol% Zn
R
R
N
H
Y
Y
5 mol% additive 1
1.5 equiv. t-BuTMG
1.5 equiv.
C−N producta
0.5 mmol
2 mL DMSO, 80 ℃, 2–8 h
N
N
N
N
N
N
CF3
O2N
MeO2C
MeO2S
Ac
NC
6 X = Br, 96% (29%)b
1 X = Br, 95% (6%)b,e
2 X = Br, 90% (9%)b,e
3 X = Br, 91% (8%)b,e
4 X = Br, 71% (10%)b,e 5 X = Br, 87% (78%)b,e
CN
N
N
N
N
N
N
N
N
N
N
N
7 X = Br, 90% (87%)b
8 X = Cl, 73% (72%)b,e 9 X = Cl, 61% (52%)d
10 X = Cl, 84% (53%)c 11 X = Cl, 88% (63%)b,e 12 X = Cl, 88% (77%)c
N
N
N
N
N
N
N
MeO
N
MeO
MeO
N
N
N
N
N
N
N
N
N
13 X = Cl, 99% (85%)b,e 14 X = Br, 86% (83%)b,e 15 X = Cl, 86% (65%)b,e 16 X = Cl, 85% (78%)b,e 17 X = Br, 89% (89%)d 18 X = Br, 89% (54%)c
CN
CF3
N
N
N
N
CO2Me
N
N
N
N
N
N
N
N
N
N
N
Cl
23 X = Cl, 80% (69%)b
19 X = Br, 64% (56%)d 20 X = Br, 74% (66%)c 21 X = Br, 65% (56%)d 22 X = Cl, 76% (77%)c
24 X = Cl, 89% (74%)c
N
N
N
S
N
N
S
N
N
CF3
N
N
MeS
N
N
N
O
N
N
N
F
26 X = Cl, 82% (77%)b 27 X = Cl, 81% (79%)b
25 X = Cl, 79% (68%)c
28 X = Cl, 93% (95%)b,e 29 X = Cl, 97% (83%)b,e 30 X = Br, 59% (44%)d
Scheme 1. Scope of (Hetero)aryl Halides for the Amination Reaction. [a] Isolated yields and in parentheses the yields of control reactions without additive. [b] 1
mol% nickel salt and 1 mol% dtbbpy. [c] 3 mol% nickel salt and 3 mol% dtbbpy. [d] 5 mol% nickel salt and 5 mol% dtbbpy. [e] 60 ºC.
3
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1–5 mol% (dppp)NiCl2
1–5 mol% dtbbpy
15 mol% Zn
R2
N
Br
R2
N
R1
R1
H
MeO2S
5 mol% additive 1
1.5 equiv. t-BuTMG
2 mL DMSO, 80 ℃, 8 h
MeO2S
1.5 equiv.
C−N producta
0.5 mmol
Me
Me
Me
NBoc
N
N
N
N
N
N
MeO2S
MeO2S
MeO2S
MeO2S
MeO2S
MeO2S
31 91% (43%)b
32 91% (38%)c
33 86% (23%)b
34 87% (66%)d
35 89% (70%)c
36 91% (26%)b
O
Me
Ph
CN
CO2Me
N
N
N
N
N
N
N
MeO2S
MeO2S
MeO2S
MeO2S
MeO2S
MeO2S
39 95% (25%)b
37 96% (53%)c
38 86% (76%)d
40 91% (79%)c
41 76% (63%)d
42 78% (57%)d
Me
F
O
OH
OMe
NH
NH
F
O
N
N
N
N
N
N
MeO2S
MeO2S
MeO2S
MeO2S
OMe
MeO2S
MeO2S
46 82% (7%)b
43 76% (33%)c
44 90% (72%)d
45 63% (8%)b,e
47 52% (31%)b,e
48 71% (47%)d
O
Me
NBoc
N
Me
N
N
N
N
N
N
N
N
N
N
N
MeO2S
MeO2S
MeO2S
MeO2S
MeO2S
MeO2S
49 88% (45%)b
52 78% (21%)b
53 89% (74%)b
50 70% (18%)b,e
51 85% (12%)b,e
54 86% (53%)b,e
Me
Me
Me
N
OMe
OMe
MeO2S
Me
N
O
N
Ph
N
N
N
Ph
OMe
MeO2S
MeO2S
MeO2S
MeO2S
MeO2S
55 82% (66%)b,e
56 67% (55%)d
57 73% (46%)c
58 84% (72%)d
59 66% (66%)d
60 74% (52%)d
Scheme 2. Scope of Secondary Amines for the Amination Reaction. [a] Isolated yields and in parentheses the yields of control reactions without additive. [b] 1
mol% nickel salt and 1 mol% dtbbpy. [c] 3 mol% nickel salt and 3 mol% dtbbpy. [d] 5 mol% nickel salt and 5 mol% dtbbpy. [e] Mn instead of Zn used.
4
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1–5 mol% (dppp)NiCl2
1–5 mol% dtbbpy
15 mol% Zn
H
N
Br
H
N
R
H
R
MeO2S
5 mol% additive 1
1.5 equiv. t-BuTMG
2 mL DMSO, 80 ℃, 8 h
MeO2S
1.5 equiv.
C−N producta
0.5 mmol
H
N
H
N
H
N
H
N
H
N
O
Ph
Ph
Me
MeO2S
MeO2S
MeO2S
MeO2S
MeO2S
61 78% (71%)c
62 73% (71%)c
63 81% (68%)c
64 82% (83%)c
65 77% (79%)c
Me
O
H
N
H
N
H
N
Me
OH
H
N
H
N
N
Me
6
5
S
3
3
MeO2S
MeO2S
MeO2S
MeO2S
MeO2S
68 75% (85%)c
66 89% (88%)c
67 82% (81%)d
69 54% (54%)d
70 89% (84%)d
Me
H
N
H
N
H
N
H
N
H
N
Me
MeO2S
MeO2S
Me MeO2S
MeO2S
OMe
Cl
MeO2S
71 88% (99%)c
73 90% (98%)c
74 83% (87%)c
75 97% (99%)c
72 83% (67%)b
H
N
OMe
OMe
H
N
Ph
H
N
OMe
H
N
H
N
MeO2S
OMe
MeO2S
MeO2S
OMe
78 99% (99%)c
MeO2S
MeO2S
Cl
76 91% (83%)c
77 94% (98%)c
79 95% (97%)c
80 95% (57%)d
F
OCF3
CF3
H
N
H
N
H
N
H
N
H
N
CF3
MeO2S
F
MeO2S
MeO2S
MeO2S
MeO2S
81 80% (85%)c
82 90% (98%)c
83 95% (97%)d
84 87% (98%)d
85 83% (75%)d
H
N
H
N
CN
H
N
H
N
H
N
CO2Me
MeO2S
CN
MeO2S
CO2Me
Ac
MeO2S
MeO2S
MeO2S
86 89% (92%)c
87 95% (99%)c
89 82% (80%)c
88 70% (75%)d
90 81% (93%)d
Scheme 3. Scope of Primary Amines for the Amination Reaction. [a] Isolated yields and in parentheses the yields of control reactions without additive. [b] 1 mol%
nickel salt and 1 mol% dtbbpy. [c] 3 mol% nickel salt and 3 mol% dtbbpy. [d] 5 mol% nickel salt and 5 mol% dtbbpy.
Gratifyingly, this C–N coupling protocol could be applied to the
primary alkyl and aryl amines successfully (Scheme 3). While the
primary alkyl amine substrates benefited moderately from the
addition of additive 1, the circumstances of anilines were much
complicated. In some cases better yields were obtained with
additive 1 (72, 76, 80 and 85), however, in the other cases the
pyridinium additive decreased the yields to some extent (71, 73,
82, 84, and 90). The primary alkyl amines bearing a diverse of
functional groups were transformed into the arylation products
efficiently (61–70). Besides, no matter with electron-donating or
withdrawing groups, anilines proved perfect substrates for the
coupling reaction (71–90). Notably, the steric congestion was well
tolerated in this coupling protocol. Anilines with ortho-substituents,
including methyl (74), methoxy (77), phenyl (79), chloro (80),
trifluoromethoxy (81), fluoro (83), trifluoromethyl (85), and cyano
(90) groups, all underwent the cross-coupling in high yields.
Then we turned our attention to the synthesis of primary
amines by this amination protocol. The cross-coupling of
ammonia and (hetero)aryl halides, however, only afforded poor
yields of desired products under the standard conditions. To our
delight, the benzophenone imine coupled with 4-bromophenyl
methyl sulfone smoothly to provide the product 91 (95%), which
could be hydrolyzed to give the primary amine 92 quantitatively
(Scheme 4).[19,20]
5
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5 mol% (dppp)NiCl2
[3]
a) C. Sambiagio, S. P. Marsden, A. J. Blacker, P. C. McGowan, Chem.
Soc. Rev. 2014, 43, 3525–3550; b) S. Bhunia, G. G. Pawar, V. Kumar,
Y. Jiang, D. Ma, Angew. Chem. Int. Ed. 2017, 56, 16136–16179; c) Q.
Cai, W. Zhou, Chin. J. Chem. 2020, 38, 879–893.
5 mol% dtbbpy
15 mol% Zn
HN
Br
N
MeO2S
MeO2S
1.5 equiv. t-BuTMG
[4]
[5]
a) S. Z. Tasker, E. A. Standley, T. F. Jamison, Nature 2014, 509, 299–
309; b) V. P. Ananikov, ACS. Catal. 2015, 5, 1964–1971.
2 mL DMSO, 80 ℃, 8 h
1.5 equiv.
91, 95% isolated yield
0.5 mmol
E. C. Hughes, F. Veatch, V. Elersich, Ind. Eng. Chem. 1950, 42, 787–
790.
NH2
1:1 1N HCl:THF (5 mL)
rt, 1 h
[6]
[7]
M. Marín, R. J. Rama, M. C. Nicasio, Chem. Rec. 2016, 16, 1819–1832.
a) J. P. Wolfe, S. L. Buchwald, J. Am. Chem. Soc. 1997, 119, 6054–6058;
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c) T. Shimasaki, M. Tobisu, N. Chatani, Angew. Chem. Int. Ed. 2010, 49,
2929–2932; d) S. D. Ramgren, A. L. Silberstein, Y. Yang, N. K. Garg,
Angew. Chem. Int. Ed. 2011, 50, 2171–2173; e) N. H. Park, G.
Teverovskiy, S. L. Buchwald, Org. Lett. 2014, 16, 220–223; f) S. Ge, R.
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E. M. Wiensch, J. Montgomery, Angew. Chem. Int. Ed. 2018, 57, 11045–
11049.
MeO2S
92, 98% isolated yield
Scheme 4. Cross-Coupling of the Hydrolysable Amine Partner.
Finally, the practical application of our C–N coupling protocol
was demonstrated by the gram-scale synthesis of Quetiapine, a
medicine used to treat certain mental/mood conditions (Scheme
5). The coupling of 11-chlorodibenzo[b,f][1,4]thiazepine and 2-(2-
(piperazin-1-yl)ethoxy)ethan-1-ol efficiently furnished 1.15 g of
Quetiapine.
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OH
O
N
OH
5 mol% (dppp)NiCl2
5 mol% dtbbpy
15 mol% Zn
Cl
O
N
N
N
N
S
N
H
S
5 mol% additive 1
1.5 equiv. t-BuTMG
1.5 equiv.
1.15 g, 99% isolated yield
3 mmol
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12 mL DMSO, 80 ℃, 8 h
Scheme 5. Gram-Scale Synthesis of Medicine Quetiapine.
In summary, we have developed a novel nickel-catalyzed
amination protocol featuring a simple Ni(II) precatalyst (1–5
mol%), an organic base (t-BuTMG) and catalytic amounts of a
pyridinium additive (5 mol%) and Zn metal (15 mol%). A diverse
of (hetero)aryl halides were coupled successfully with primary and
secondary alkyl amines, and anilines to furnish the corresponding
amination products in good to excellent yields. Generally,
moderate to high promoting effect of catalytic pyridinium additive
was observed on the Ni-catalyzed C–N coupling reaction. Further
exploration into the reaction mechanism is undergoing in our lab.
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Acknowledgements
Financial support was provided by Natural Science Foundation of
Shanghai (19ZR1468700), CAS Key Laboratory of Synthetic
Chemistry of Natural Substances, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences.
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Keywords: nickel-catalyzed • amination • C–N coupling • aryl
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10.1002/chem.202002800
Chemistry - A European Journal
COMMUNICATION
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imine in our amination protocol.
7
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10.1002/chem.202002800
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
R2
N
1–5 mol% NiCl2–dtbbpy
R
X
I
R2
N
15 mol% Zn
R1
N
R
R
Me
R1
5 mol% additive
H
Y
Y
additive
amine
C−N product
aryl halide
1.5 equiv. t-BuTMG
Pyridinium salt gives a hand to nickel. A Ni-catalyzed amination has been developed as an efficient synthetic tool of promising
potential for application in industry. A diverse of (hetero)aryl halides were coupled successfully with primary and secondary alkyl
amines, and anilines in good to excellent yields. This C–N coupling features with low NiCl2–dtbbpy loadings, catalytic amounts of Zn
metal and a pyridinium additive, and an organic base.
Keywords: nickel-catalyzed; amination; C–N coupling; aryl halides; anilines
8
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