Nickel-catalyzed C-N bond reduction of aromatic and benzylic quaternary ammonium triflates

Article abstract of DOI:10.1039/c6cc04531f

A nickel-catalyzed, efficient C-N bond reduction of aromatic and benzylic ammonium triflates has been developed using sodium isopropoxide as a reducing agent. The high efficiency, mild conditions, and good compatibility with various substituents made this method an effective supplement to the current catalytic hydrogenation reactions. Combining this reductive deamination reaction with directed aromatic functionalization reactions, a powerful strategy for regioselective functionalization of arenes was demonstrated using dialkylamine groups as traceless directing groups.

Full text of DOI:10.1039/c6cc04531f

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Nickel-Catalyzed C-N Bond Reduction of Aromatic and Benzylic
Quaternary Ammonium Triflates
Received 00th January 20xx,
Accepted 00th January 20xx
Yuan-Qiu-Qiang Yi, Wen-Cheng Yang, Dan-Dan Zhai, Xiang-Yu Zhang, Shuai-Qi Li and Bing-Tao
Guan*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A nickel-catalyzed, efficient C-N bond reduction of aromatic and reported so far had been mostly limited in the catalytic
6
benzylic ammonium triflates has been developed using sodium hydrogenation of benzylic amines (Scheme 1, eq 1). In 2009,
isopropoxide as a reducing agent. The high efficiency, mild MacMillan and coworkers achieved the first C-N bond
conditions, and nice compatibility with various substituents made reductive deamination of aryl quaternary ammonium salts
this method an effective supplement to the current catalytic using sodium metal as the reducing agent in liquid ammonia at
7
hydrogenation reactions. Combining this reductive deamination -78˚C (Scheme 1, eq 2). Herein, we report a nickel-catalyzed
reaction with directed aromatic functionalization reactions, a C-N bond reduction of aromatic and benzylic quaternary
powerful strategy for regioselective functionalization of arenes ammonium salts with sodium isopropoxide as an efficient
was demonstrated using dialkylamine groups as traceless directing reducing agent .
Previous Work:
groups.
H2
H
The activation of traditionally unreactive chemical bonds as
synthetic precursors had attracted much attention, and rapid
NR
2
(eq 1)
(eq 2)
R'
R'
R'
Pd/C
1
progress had been made in the past decades. The C-N bond is
NR
2
H
one of the most elementary and universal chemical bonds. The
cleavage of C-N bonds, especially the unreactive ones, had
2
scarcely been developed. Kakiuchi and coworkers reported a
1) MeI or MeOTf
3
R'
2) Na/NH , -78 °C
This Work:
ruthenium-catalyzed C-N bond activation of anilines directed
3
by the ortho carbonyl group. Chatani and coworkers recently
1
) MeOTf
n
NR2
n H
(eq 3)
R'
R'
reported a nickel-catalyzed C-N bond reduction and borylation
4
of N-aryl amides and carbamates. The quaternary ammonium
2) i-PrONa
Ni catalyst
n = 0, 1
salts offered an alternative strategy for the catalytic Scheme 1 Reductive Deamination of Anilines and Benzylic
5
functionalization of unreactive C-N bonds. Pioneering work Amines
reported in 1988 by Wenkert and coworkers showed that
Various methods had been developed to transform aryl
nickel catalysts could achieve the cross-coupling reaction halides into simple arenes with reductants such as H
2
,
8
-11
between aromatic quaternary ammonium salts and Grignard hydrides, Grignard reagents, etc.
In particular, alkoxides
5
a
reagents. Later in 2003, MacMillan and coworkers advanced also proved to be efficient and practical reductants for the
the reaction to realize the first Suzuki coupling reaction of dehalogenation of aryl iodides, bromides, chlorides and even
5
b
12
aryltrimethylammonium triflates.
transformations such as arylation, amination, borylation and catalyst in the activations of unreactive chemical bonds,
Very recently, various fluorides. On the basis of the excellent performance of nickel
5
c-k
13
even carboxylation with CO2 had been developed.
Even especially in the catalytic reduction of inert C-O bonds , we
though, the removal of the nitrogen-contained groups was still further proposed that a nickel catalyst combined with an
to be developed. The reductive deamination reaction studies alkoxide could effect the catalytic reduction of quaternary
ammonium salts.
We initiated our study with 2-naphthyltrimethylammonium
12c
triflate under Fort’s conditions , and only 30% yield of
State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative
Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin,
reduced product was obtained (Table 1, entry 1). The use of
3
*
00071, China
Corresponding author: e-mail: guan@nankai.edu.cn
3
PCy ligand or other nickel(II) catalysts did not make any
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
significant improvements (Table 1, entries 2-4), which might
hint that the active nickel(0) species was not easily produced
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from the nickel(II) precursors under present reaction conditions, and the reduced product naphthalene was
conditions. Therefore, with the direct use of Ni(cod) as a obtained in excellent yields (See ESI). Those results indicated
2
catalyst, the catalytic reduction reaction could take place that different kinds of dialkylamine groups could serve as
smoothly with various kinds of ligands (Table 1, entries 5-11). leaving groups to achieve the reductive cleavage, which would
3
It is important to note that either 20% of PCy or 10% of make this method a general process for the reductive
Me
imidazolium chloride IMes ·HCl as ligand could achieve the deamination reaction.
reaction quantitatively after heating for 2 hours (Table 1,
a
entries 5 and 11). We next examined the reaction with less Table 2 Scope of Aryl Ammonium Triflates
sodium isopropoxide (2.5 equiv), and only 82% yield of
reduced product was obtained (Table 1, entry 12). Lithium and
potassium isopropoxides could also smoothly drive the
catalytic reduction reaction, but lead to lower yields (Table 1,
entries 13-14). Other sodium alkoxides such as methoxide,
ethoxide and propoxide were also subjected to the reaction,
and reduced products were obtained in much lower yields
(Table 1, entries 15-17). Sodium tert-butoxide, an alkoxide
without β-hydrogens, could hardly afford any reduction
product (Table 1, entry 18).
a
Table 1 Effect of Reactions Parameters
Entry Ni catalyst
ligand
RONa
Yield
b
(
%)
c
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
Ni(acac)2
IMes•HCl
PCy3
i-PrONa 30
i-PrONa <5
i-PrONa <5
i-PrONa 37
a
Conditions: aryl ammonium triflate
Me
mol %), IMes •HCl (10 mol %), i-PrONa (1.2 mmol), dioxane
1
2
(0.4 mmol), Ni(cod) (10
Ni(acac)2
NiCl •glyme
2
PCy3
b
2 mL), 100 ˚C, 2 h. Isolated yields. 20% PCy
c
as ligand. GC
(
3
NiCl (PCy )
2
--
3 2
d
d
yields with dodecane as an internal standard. Mixture of
reduction products (E : Z : 1,2-diphenylethane = 10 : 7 : 1) from
Ni(cod)2
PCy3
i-PrONa 99
i-PrONa 58
i-PrONa 50
i-PrONa 68
i-PrONa 80
i-PrONa 83
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
PPh3
4
-styrylphenyl ammonium triflate 1m (E : Z = 1 : 1).
Using PCy as ligand, we further carried out the reduction
dppe
3
IPr•HCl
IMes•HCl
Me
reaction with 1-naphthyltrimethylammonium triflate, and
naphthalene was obtained in 83% yield (Table 2, 2a). para-
Butyl substituted phenyl ammonium triflate was treated under
this condition, however, only 29% yield of butylbenzene was
obtained. After further ligand screening, the N-heterocyclic
0
1
2
3
4
5
6
7
8
IMes •HCl
Me
IMes •HCl
e
i-PrONa 95
i-PrONa 82
f
PCy3
Ni(cod)2
PCy3
i-PrOLi
i-PrOK
MeONa
EtONa
PrONa
90
82
14
39
55
Me
carbene precursor IMes ·HCl was found to be able to drive
Ni(cod)2
PCy3
the reduction efficiently and afford butylbenzene in 71% yield
Me
Ni(cod)2
PCy3
(Table 2, 2b) (See ESI). With IMes ·HCl as the ligand
Ni(cod)2
PCy3
precursor, we then expanded the substrate scope to various
substituted phenyl ammonium triflates. Methyl and phenyl
substituted phenyl ammonium triflates could undergo the
reduction reaction and generate the corresponding products in
Ni(cod)2
Ni(cod)2
PCy3
PCy3
t-BuONa <5
good yields (Table 2, 2c-2d). It is worth noting that steric
hindrance from the ortho methyl group do not affect the
reduction reaction much. Ether fragments such as methoxyl,
phenoxyl and benzyloxyl group were well compatible with
a
Conditions: 2-naphthyl ammonium triflate 1a (0.2
mmol), Ni catalyst (10 mol %), ligand (20 mol %), RONa
b
0.6 mmol), dioxane (1 mL), 100 ˚C, 12 h. GC yields with
present conditions (Table 2, 2e-2g). The cyano group survived
(
well under the reduction conditions: 4-cyanophenyl
ammonium triflates underwent the catalytic reduction
reaction to afford benzonitrile in 75% yield (Table 2, 2h).
Aromatic ammonium triflates with some nitrogen containing
groups were also subjected to the reaction, and the products
c
dodecane as an internal standard. THF as solvent, 65 ˚C.
d
e
hours. 10 mol % ligand, 2 hours. i-PrONa (0.5 mmol).
f
2
2-Naphthyl ammonium iodide and 2-naphthyl ammonium
triflates from 2-naphthyl pyrrolidine, piperidine and
morpholine were also tested under present reaction
were obtained in moderate to good yields (Table 2, 2i-2l). The
2
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indole, amide and carbamate structures remained intact reported here, the dialkylamine groups could serve as
during the reaction. Styryl and carbonyl groups, including acyl traceless directing groups for the regioselective
groups, alkoxycarbonyl and alkyl carbamoyl groups, could well functionalization reactions of arenes. To test our hypothesis
be tolerated in the reaction (Table 2, 2m 2p). The compatibility further, we designed and synthesized a meta-methyl biphenyl
with the functional groups such as alkene, benzyl ether, compound 2q from easy available dimethyl-o-toluidine (Table
carbonyl and benzonitrile units, which are reactive under 4). The direct bromination of dimethyl-o-toluidine with NBS
general catalytic hydrogenation conditions, enables this took place selectively at the para-position of the amino group
process to be a practical approach for selective reductive to afford aryl bromide . The palladium-catalyzed Suzuki
coupling of the aryl bromide gave a biaryl product in 86%
-
4
5
cleavage of C-N bond.
5
6
a
Table 3 Scope of Benzylic Ammonium Triflates
yield. The following quaternization and nickel-catalyzed
reduction reaction could easily erase the amino group to
afford meta-methyl biphenyl compound 2q in good yield. This
synthesis successfully demonstrated the potential of the
present reduction method as a powerful strategy for the
regioselective functionalization of arenes.
NMe3OTf
H
Ni(cod)2 (10 mol %)
IMesMe•HCl (10 mol %)
R'
R'
R
+
i-PrONa
R
dioxane, 100 °C, 2 h
1
3
Table 4 Synthetic Application
H
H
H
H
H
H
Me
NMe2
Me
H
t-Bu
Ph
BnO
NMe2
a 99%b
3b 89%b
NMe2
3
3c 84%
3d 78%
Me
Me
a) 92%
b) 86%
c) 74%
d) 84%
H
H
H
Br
4
N
F3C
F3C
F
F3C
NC
5
6
2q
Bn
3
e 85%b,c
3f 83%b
3g 70%b
3h 82%
Conditions: a) NBS (1 equiv), NH OAc (10 mol %), CH CN, rt, 10
3
4
H
O
min; b) (4-trifluorophenyl)boronic acid (1.2 equiv), [Pd(PPh ) ]
3 4
H
(
(
2 mol %), K PO (2 equiv), MeOH/H O, 100 ˚C , 20 h; c) MeOTf
3
4
2
+
1.2 equiv)，Et O, reflux, overnight; d) Ni(cod) (10 mol %),
2 2
Me
Ph
Ph
IMes ·HCl (10 mol %), i-PrONa (3 equiv), dioxane, 100 ˚C, 2 h.
3
i 69%
3j 51% (1 : 3)
2n 54%b
a
Conditions: benzylic ammonium triflate
Me
10 mol %), IMes •HCl (10 mol %), i-PrONa (1.2 mmol),
1
(0.4 mmol), Ni(cod)2
(
b
dioxane (2 mL), 100 ˚C, 2 h. Isolated yields. GC yields with
c
dodecane as an internal standard. 80 ˚C.
To examine the substrate scope further, several benzylic
ammonium triflates were tested under the optimized
conditions. Those results are summarized in Table 3. Various
functional groups such as benzyloxyl, fluoro, trifluoromethyl
and cyano groups survived well under the reduction
conditions, and the products were obtained in moderate to
Scheme 2 Deuterated Experiment
To probe the mechanism of the present process further, we
carried out the reduction of the biphenyl ammonium triflate
with a deuterated sodium isopropoxide (Scheme 2). The
deuterated biphenyl product 2d-D was obtained in excellent
yield, which confirmed that sodium isopropoxide was the
hydrogen donor of the reduction reaction. The initial reaction
rates were further measured separately using i-PrONa and i-
good yields (Table 3, 3a-3h). Branched benzylic ammonium
triflates were also subjected to the reduction reaction.
Another phenyl group at the benzylic position showed little
effect on the reaction, and the reduced product,
diphenylmethane, was obtained in a yield of 69% (Table 3, 3i).
However, a methyl group at the benzylic position easily led to
a mixture of a reduction product and an elimination product
7
PrONa-D as the reducing agent under exact same conditions,
and a kinetic isotope effect of 1.06 was observed, suggesting
that the β-hydride elimination is not the rate-determining step.
On the basis of those observations and the mechanism studies
reported previously, we propose a similar process as the
nickel-catalyzed reduction of aryl halides. Oxidative addition of
the ammonium triflates to Ni(0) catalyst would start the
catalytic cycle. The following anion displacement and β-H
elimination produce a nickel hydride intermediate, which
could easily undergo the reductive elimination to give the
reduced product and regenerate the reactive Ni(0) species.
In summary, we have developed an efficient method for C-N
bond reduction of aromatic and benzylic ammonium triflates
using nickel(0) catalyst and sodium isopropoxide as a reducing
reagent. The present reduction is compatible with a wide
range of oxygen-, nitrogen-, and carbonyl-containing
substituents, some among which are highly reactive under
(Table 3, 3j), which hinted that a competing transmetalation
and β-hydride elimination happened to a nickel intermediate.
It is interesting to note that benzoyl methylene ammonium
triflate also underwent the reduction reaction smoothly to
afford acetophenone in moderate yield (Table 3, 2n).
Aromatic or benzylic amines are among the most common
structural units and display diverse reactivities. Dialkylamine
groups are among the most powerful electron-donating
substituents and most effective directing groups which could
facilitate various aromatic functionalization reactions with
good efficiency and regioselectivity. Thanks to the nickel-
catalyzed reduction of quaternary ammonium triflates
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general hydrogenation conditions. Therefore, the nickel-
catalyzed C-N bond reduction of aromatic and benzylic
ammonium triflates reported here could be an effective
supplement to current catalytic hydrogenation reactions. In
combination with the directed functionalization of anilines and
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5
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