Arylation of Azaarylmethylamines with Aryl Chlorides and a NiBr2/NIXANTPHOS-based Catalyst

Article abstract of DOI:10.1002/adsc.201700438

A nickel-catalyzed coupling of azaarylmethylamines with aryl chlorides has been achieved. NIXANTPHOS together with low cost NiBr₂ was successfully developed and optimized to exhibit high reactivity at 2.5 mol % loading. Under optimized reaction

Full text of DOI:10.1002/adsc.201700438

Title: Arylation of Azaarylmethylamines with Aryl Chlorides and a
NiBr2/NIXANTPHOS-based Catalyst
Authors: Gui Gao, Yue Fu, Minyan Li, Bo Wang, Bing Zheng, Shicong
Hou, and Patrick J. Walsh
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700438
Link to VoR: http://dx.doi.org/10.1002/adsc.201700438

Advanced Synthesis & Catalysis
10.1002/adsc.201700438
Update
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Arylation of Azaarylmethylamines with Aryl Chlorides and a
NiBr /NIXANTPHOS-based Catalyst
2
a
b
b
a
, a
a
Gui Gao, Yue Fu, Minyan Li, Bo Wang, Bing Zheng,* Shicong Hou, Patrick J.
,
b
Walsh*
a
Department of Applied Chemistry, China Agricultural University, Beijing 100193, P. R. China. E-mail:
014026@cau.edu.cn.
Roy and Diana Vagelos Laboratories, Penn/Merck Laboratory for High-Throughput Experimentation, Department of
Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.
E-mail: pwalsh@sas.upenn.edu.
2
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract.
azaarylmethylamines with aryl chlorides has been situ deprotonation of (aminomethyl)pyridines
achieved. NIXANTPHOS together with low cost NiBr
A
nickel-catalyzed
coupling
of for the synthesis of aryl(azaaryl)methylamines via in-
2
was followed by arylation with aryl bromides (Scheme 1).
successfully developed and optimized to exhibit high This umpolung approach directly provides the
reactivity at 2.5 mol % loading. Under optimized reaction arylated tertiary amines without protecting groups or
conditions, aryl(azaaryl)methylamine products were
afforded in good to excellent yields (22 examples, up to
additional activating groups.
9
8% yield).
Keywords: NIXANTPHOS; NiBr
2
; Arylation;
Azaarylmethylamines; Aryl Chlorides
Aryl(azaaryl)methylamines are widely found in
pharmaceuticals, bioactive substances and as ligands
for metal complexes.[
1]
They have attracted
significant attention due to their diverse activity
against tumors,[ viruses, HIV, tuberculosis,
2]
[3]
[4]
[5]
[6]
iron metabolic disorders, and cortisol dependent
diseases.[
aryl(azaaryl)methylamines are illustrated in Figure 1.
Classic approaches to the synthesis of
aryl(azaaryl)methylamines include addition of
7]
Some
prominent
examples
of
Figure 1. Examples of aryl(azaaryl)methylamines in
pharmacologically active compounds.
[8]
organometallic reagents to aldimines,
ketimine
reduction[ and C–N coupling reactions.
9]
[10]
An
intramolecular aryl rearrangement to give
aryl(azaaryl)methylamines was also reported by
Clayden and coworkers.[ These approaches usually
required prefunctionalized starting materials or
organolithium reagents, which can limit their scope.
11]
Our group, among others, has strived to develop
methods for the catalytic functionalization of weakly
3
acidic sp –hybridized C–H bonds via
deprotonative–cross–coupling process (DCCP).
a
[
12]
These
reactions
involve
reversible
in-situ
deprotonation of the substrates (pronucleophiles) to
generate reactive nucleophiles that undergo
transmetallation with the catalyst. Considering the
value of aryl(azaaryl)methylamines, we recently
introduced an efficient palladium-catalyzed approach
Scheme 1. Pd-catalyzed arylation of azaarylmethylamines
with aryl bromides involving reversible in-situ
deprotonation of the substrate (aminomethyl)azaarenes.
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201700438
The catalyst for this reaction was based on van
1a and 4-tert-butyl chlorobenzene 2b with ligand
screening on microscale. A total of 44 electronically
diverse mono- and bidentate phosphines were
Leeuwen’s NIXANTPHOS ligand,[ which we have
shown imparts enhanced reactivity to palladium
catalysts under basic conditions where the ligand’s
N–H is deprotonated.[ We were curious if the
enhanced reactivity of (NIXANTPHOS)Pd catalysts
would translate to other transition metals. We
therefore examined the arylation of 2-pyridylmethyl
13]
examined using Ni(COD)
2
as metal source,
14]
LiN(SiMe as base, and CPME (cyclopentyl methyl
)
3 2
o
ether) as solvent at 110 C for 12 h (see Supporting
Information pg S2 for details). The two most
promising ligands from this screen were
[17]
amine with bromobenzene and LiN(SiMe
3
)
2
in the
NIXANTPHOS (L1) and JohnPhos (L2).
continued with a second lab scale (0.1 mmol) screen
examining nickel sources [NiBr Cp Ni,
Cl Ni(PPh and Ni(COD) (5 mol % each)],
NIXANTPHOS and JohnPhos, and 3 solvents
[CPME, dioxane and toluene] with LiN(SiMe , 110
We
presence of 37 of the most common ligands in cross-
coupling chemistry.[
15]
As shown in Scheme 2, the
2
,
2
catalyst derived from Ni(COD) and NIXANTPHOS
proved to be the most active, giving the arylation
2
2
3
)
2
2
[16]
product in 93% isolated yield. Although only one
pyridylmethylamine was examined with the
Ni(NIXANTPHOS)-based catalyst, the results
appeared promising.
3 2
)
o
C for 12 h (see Supporting Information pg S5 for
details). The top Ni/ligand/solvent combination from
this screen was NiBr
affording product 3ab in 97% assay yield (AY)
Table 1, entry 1). Reducing the catalyst loading to
2
/NIXANTPHOS/toluene,
(
1
0 mol % Ni(COD)2
Ph
2.5 and 1 mol % led to 95 and 43% AY (entries 2 and
3). Next, we examined the impact of temperature and
N
10 mol % Ligand
+
Ph–Br
N
N
O
o
LiN(SiMe3)2 (3 equiv)
CPME, 100 oC, 16 h
N
O
found the AY dropped to 75% at 80 C (entry 4).
Reducing the base equivalents from 2 to 1 equiv. led
to a significant drop in yield to 22% AY (entry 2).
Changing the reaction concentration from 0.1 M to
1
equiv
1.2 equiv
Best ligand: NIXANTPHOS 93% yield
Scheme 2.
pyridylmethyl morpholine with bromobenzene using
Ni(COD) /NIXANTPHOS catalyst.
Preliminary result of arylation of 2-
0
.2 M or 0.05 M resulted in a drop in the AY’s (76
and 80% yield, entries 5 and 6, respectively).
2
Table
1.
Optimization
of
α-arylation
of
An advantage of nickel catalysts over their
palladium counterparts is the substantial decrease in
cost of Earth-abundant nickel. That said, however,
a, b
azaarylmethylamine 1a with ArCl 2b.
Ni(COD)
2
is far from ideal, because it is both
expensive and requires special handling precautions
due to its air-sensitivity. To improve upon the
palladium-based arylation of azaarylmethylamines in
Scheme 1, we desired to develop a nickel-based
catalyst using a readily available, air-stable, and
inexpensive nickel source. Once identified, we
planned to expand the scope beyond the singular
nickel-catalyzed example in Scheme 1, and to focus
on more economical aryl chlorides.
Entry
NiBr
mol %)
5/7.5
2.5/3.75
1/1.5
2.5/3.75
2.5/3.75
2.5/3.75
2
/L
Conc.
(M)
0.1
0.1
0.1
0.1
0.05
0.2
Temp
( C)
Assay yield
o
(
(%)
1
2
3
4
5
6
110
110
110
80
110
110
97
95(22 )
43
c
75
76
80
Herein, we report a highly efficient α-arylation of
(
aminomethyl)pyridines with aryl chlorides using a
catalyst formed from NiBr
Scheme 3).
2
and NIXANTPHOS
[
a]
Reactions conducted on a 0.1 mmol scale using 1 equiv
(
[
b]
of 1a, 2 equiv of LiN(SiMe
Yields determined by H NMR spectroscopy of the crude
reaction mixtures on a 0.1 mmol scale.
LiN(SiMe
3
)
2
, and 1.2 equiv of ArCl.
1
[
c]
1 equiv. of
3 2.
)
With the optimized conditions in hand (Table 1,
entry 2), the scope of 4-(pyridin-2-ylmethyl)
morpholine 1a and different aryl chlorides 2 was
explored (Table 2). The product 3aa was generated
from chlorobenzene in 95% yield. Replacing aryl
chloride 2a with its aryl bromide counterpart 2a’ led
to a drop in the yield to 79%. It should be noted,
however, that these conditions were optimized for
Scheme 3. This work.
Our previous study in Scheme 2 used only
bromobenzene as the electrophile. Therefore, using
High Throughput Experimentation (HTE) techniques
on a 10 umol scale, we initiated studies of the
coupling between 4-(pyridin-2-ylmethyl) morpholine
t
aryl chlorides. Alkyl substituted aryl chlorides 4- Bu
(
2b) and 4-methyl (2c) also furnished products in
excellent yields (90 and 89%, respectively, for 3ab
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201700438
and 3ac). Electron rich 4-chloroanisole (2d) was
successfully coupled, delivering 3ad in 93% yield. 4-
Fluorochlorobenzene (1e) also underwent coupling in
Next, we examined the coupling reactions of various
acyclic amines with aryl chloride 2b (Table 3). When
the 2-pyridyl amine was changed from morpholine to
61% yield to provide 3ae, although the Ni loading
N,N-dimethyl-
corresponding products 3bb and 3cb were obtained in
3 and 86% yield, respectively. Under the same
and
N,N-diethylamine
the
had to be increased to 5 mol %. The sterically
hindered 1-naphthyl chloride reacted in 62% yield to
provide the expected product (3af). Aryl chlorides
bearing either 3-methyl or 3-trifluoromethyl groups
were suitable cross-coupling partners, furnishing tolyl
9
conditions, pyrrolidine thiomorpholine and N-
methylpiperazine were coupled, generating aryl(2-
pyridyl)methylamines in 90, 73, and 82% yield,
respectively. In order to achieve a broader scope for
our protocol, we examined 4-pyridyl methylamines.
N,N-Dimethyl-1-(pyridin-4-yl)methanamine (1g) and
the morpholine analogue (1h) coupled with 4-tert-
butyl chlorobenzene to form the desired products 3gb
and 3hb in 60 and 89% yield, respectively. In
addition, 1-methyl-4-(pyridin-4-ylmethyl)piperazine
(
3ag) and trifluorotolyl (3ah) products in 88 and 98%
yield, respectively. The substrate 4-
chlorobenzophenone could undergo addition of the
lithiated pyridyl amine to the carbonyl group. We
were pleased to find, however, that the
Ni(NIXANTPHOS)-based system exhibited excellent
selectivity,
providing
the
diarylmethylamine
derivative (3ai) in 86% yield. Heteroaromatic 3-
chloropyridyl participated in the coupling reaction
with 1a to afford 3aj, albeit in 33% yield (despite
substantial effort to optimize this substrate). Finally,
coupling of 1a with aryl chloride bearing an
acetamide group (2k) afforded products 3ak in 53%
yield.
(
1i) furnished product 3ib in 97% yield. Despite
significant optimization, the 3-pyridylmethyl amine
4-(pyridin-3-ylmethyl)morpholine yield could not be
raised above 61%. The isoquinoline derivative N,N-
dimethyl-1-(quinolin-2-yl)methanamine
furnished the coupling product 3kb in 80% yield. N-
Methyl-N-(pyridin-2-ylmethyl)aniline (1l)
underwent coupling to provide the product 3lb in
6% yield with 10 mol % catalyst. We tested the
(1k)
Table 2. Substrate scope of aryl chlorides in the arylation
of 4-(pyridin-2-ylmethyl)morpholine 1a.a
5
coupling of benzyl amine with 2b, however, no
product could be observed and starting material was
recovered. The C-N coupling (Buchwald-Hartwig
coupling) was also not observed.
Table 3. Substrate scope of azaarylmethylamines in the
arylation of aryl chloride 2b.a
[
a]
Reactions conducted on a 0.1 mmol scale using 1 equiv
of 1a, 2 equiv of LiN(SiMe , and 1.2 equiv of ArCl.
Isolated yields after chromatographic purification.
3 2
)
[
b]
5
mol % Ni. [ 10 mol % Ni. 4 equiv of LiN(SiMe
c]
[d]
)
3 2
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201700438
Finally, a key finding of this work is that the
combination of nickel and NIXANTPHOS
outperformed other nickel ligand combinations in the
coupling of azaarylmethylamines with aryl chlorides
under the conditions examined. These results suggest
that the high reactivity of the Pd(NIXANTPHOS)
catalyst under conditions where the NIXANTPHOS
N–H is deprotonated are translatable to nickel and
perhaps other metals. We are currently exploring this
hypothesis as well as attempting to develop an
enantioselective version of this reaction.
Experimental Section
1
.
General procedure for the arylation of
azaarylmethylamines.
An oven-dried microwave vial equipped with a stir bar was
charged with LiN(SiMe ) (66.9 mg, 0.4 mmol, 2.0 equiv)
3 2
under a nitrogen atmosphere in the glovebox. 4-(Pyridin-2-
ylmethyl)morpholine (35.6 mg, 0.2 mmol, 1.0 equiv) and
4
-t-Bu-chlorobenzene (40.5 mg, 0.24 mmol, 1.2 equiv)
were added by syringe in the glovebox. Next, 1 mL stock
solution containing NiBr (1.1 mg, 0.005 mmol) and
2
NIXANTPHOS (4.2 mg, 0.0075 mmol) in toluene was
added under a nitrogen atmosphere via syringe in the
glovebox. The microwave vial was sealed with a cap and
o
the reaction was stirred at 110 C for the specified time
then allowed to cool to room temperature. The reaction
mixture was quenched with H O (0.2 mL) and passed
2
through a short pad of silica gel and eluted with ethyl
acetate (1 mL * 3). The combined organics were
concentrated in vacuo. The crude residue was purified by
flash column chromatography to yield the monoarylated
azaarylmethylamine derivatives 3.
[
a]
Reactions conducted on a 0.1mmol scale using 1 equiv
of 1b-1i, 2 equiv of LiN(SiMe , and 1.2 equiv of ArCl.
Isolated yields after chromatographic purification.
3 2
)
[
b]
10
mol % Ni. [ 5 mol % Ni.
c]
In order to investigate the potential scalability of
our protocol (Scheme 4), we conducted the arylation
of 4-(pyridin-4-ylmethyl)morpholine 1h with 4-tert-
buty chlorobenzene 2b on gram scale. The desire
coupled product 3hb was isolated in 84% yield (2.09
g).
2
. Procedure for the gram scale synthesis.
An oven-dried 100 mL Schlenk tube equipped with a stir
bar was charged with 4-(pyridin-4-ylmethyl)morpholine 1h
(
1.44 g, 8.0 mmol). The Schlenk tube was sealed with a
rubber septum and was connected to a Schlenk line,
evacuated, and refilled with nitrogen (repeated three times).
A solution (prepared in the glove box) of aryl chloride 2b
(
2.70 g, 16.0 mmol) in 5 mL anhydrous toluene was added
to the Schlenk tube via syringe through the rubber septum.
A solution (prepared in the glove box) containing NiBr
Scheme 4. Gram scale synthesis of 3hb.
2
In conclusion, we report an efficient nickel-
catalyzed arylation of azaarylmethylamines with aryl
chlorides. Various aminomethyl azaarenes and aryl
chlorides are easily coupled to provide attractive
intermediates for the synthesis of biologically active
compounds. The most significant advance is
replacing palladium with an inexpensive and easily
(44 mg, 0.2 mmol) and NIXANTPHOS (168 mg, 0.3 mmol)
in 5 mL anhydrous toluene was added to the Schlenk tube
via syringe through the rubber septum. Next, a solution of
3 2
LiN(SiMe ) (2.68 g, 16.0 mmol) in 30 mL anhydrous
toluene was added by syringe through the rubber septum.
º
The reaction mixture was stirred for 16 h in total at 110 C,
2
opened to air, and quenched with 10 mL of H O. The
layers were separated and the aqueous layer was extracted
with DCM (3X10 mL). The combined organic layers were
concentrated in vacuum. The crude material was loaded
onto a deactivated silica gel column via pipette and
purified by flash chromatography on silica gel (eluted with
handled nickel source, NiBr . In several cases, the
2
loading of the nickel-based catalyst is lower than the
palladium analogue.
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201700438
Methanol : DCM = 1:30) to give the product (2.09 g, 84%
yield) a white solid. The H and C{ H} NMR data for
this compound match the literature data.
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Acknowledgements
6
649.
We thank the National Science Foundation (CHE-1464744) and
National Institutes of Health (NIGMS 104349) for financial sup-
port. BZ thanks the Chinese Universities Scientific Fund
[5] R. S. Upadhayaya, J. K. Vandavasi, N. R. Vasireddy, V.
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(
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Program (201610019084). GG thanks the National Key
Technology Research and Development Program (No.
[
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015BAK45B01) for the financial support.
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Advanced Synthesis & Catalysis
10.1002/adsc.201700438
COMMUNICATION
Arylation of Azaarylmethylamines with Aryl
Chlorides and a NiBr
Catalyst
2
/NIXANTPHOS-based
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Gui Gao, Yue Fu, Minyan Li, Bo Wang, Bing
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Zheng,* Shicong Hou, Patrick J. Walsh*
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