Development of an air-stable nickel precatalyst for the amination of aryl chlorides, sulfamates, mesylates, and triflates

Article abstract of DOI:10.1021/ol403209k

A new air-stable nickel precatalyst for C-N cross-coupling is reported. The developed catalyst system displays a greatly improved substrate scope for C-N bond formation to include both a wide range of aryl and heteroaryl electrophiles and aryl, heteroaryl, and alkylamines. The catalyst system is also compatible with a weak base, allowing the amination of substrates containing base-sensitive functional groups.

Full text of DOI:10.1021/ol403209k

Letter
pubs.acs.org/OrgLett
Development of an Air-Stable Nickel Precatalyst for the Amination of
Aryl Chlorides, Sulfamates, Mesylates, and Triflates
Nathaniel H. Park, Georgiy Teverovskiy, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139,
United States
S
* Supporting Information
ABSTRACT: A new air-stable nickel precatalyst for C−N cross-coupling is
reported. The developed catalyst system displays a greatly improved substrate
scope for C−N bond formation to include both a wide range of aryl and
heteroaryl electrophiles and aryl, heteroaryl, and alkylamines. The catalyst
system is also compatible with a weak base, allowing the amination of substrates
containing base-sensitive functional groups.
Scheme 1. Synthesis of (dppf)Ni(o-tolyl)Cl (2)
he development of a general, robust, and operationally
T
simple catalyst system for Ni-catalyzed C−N cross-
coupling reactions has remained a significant challenge despite
16 years of extensive catalyst development. After our first
report,1 many groups have expanded Ni-catalyzed C−N cross-
coupling to include new electrophiles such as aryl tosylates,
carbamates, sulfamates, methyl ethers, phosphates, pivalates,
and nitriles.2−4 However, many of these systems rely on air-
and moisture-sensitive Ni(COD)2 as a catalyst precursor.1,3
While other catalyst systems have utilized air-stable Ni(II)
sources, many of these systems required the use of an external
reductant to generate the catalytically active Ni species.2c,5
Additionally, the overall substrate scope of all Ni-catalyst
systems reported to date has remained relatively limited, with
only a few successful examples of substrates containing base-
sensitive functional groups.6−9 To address these challenges we
sought to develop an air-stable, highly active Ni(II) precatalyst
for C−N cross-coupling reactions.
be air-stable.16 A crystal structure of 2 shows a cis-ligated nickel
dppf complex with square planar geometry (Figure 1).17
Ni(II)−(σ-aryl) complexes, first reported by Shaw in 1960,
were shown to be robust compounds, stable to moisture and
air.10 In 2007, Yang reported the first use of these complexes in
C−N cross-coupling by demonstrating that (Ph3P)2Ni(1-nap)
Cl used in combination with an N-heterocyclic carbene ligand
(IPr·HCl) generated an effective catalyst system for the
amination of aryl chlorides.11−13 Based on these precedents14
and our previous success using dppf as a supporting ligand in
Ni-based catalysis,1 we sought to investigate the use of a dppf-
ligated Ni(II)−(σ-aryl) complex as a precatalyst in C−N bond-
forming reactions.
For our study, we selected (dppf)Ni(o-tolyl)Cl (2) as a
precatalyst for C−N bond formation (Scheme 1). The
synthesis of 2 can be accomplished by exchanging the
triphenylphosphine ligands on (Ph3P)2Ni(o-tolyl)Cl (1) with
dppf in THF at room temperature, resulting in an 83% yield
(Scheme 1). (Ph3P)2Ni(o-tolyl)Cl (1) can be easily prepared
directly from commercially available (Ph3P)2NiCl2.15 Similar to
other Ni(II)−(σ-aryl) complexes,2a,b,5j,10,12−14 2 was found to
Figure 1. X-ray crystal structure of (dppf)Ni(o-tolyl)Cl (2)
(representation from two different angles). THF molecule and
hydrogen atoms are omitted for clarity.
Having prepared and characterized 2, we set out to
investigate its use as a precatalyst in the amination of 4-n-
butylchlorobenzene (3) with morpholine (4) (Table 1).
Performing the reaction using 5 mol % of 2 and 5 mol % of
dppf as the catalyst with NaOtBu as the base in CPME for 15
min at 100 °C resulted in a 10% yield (entry 1, Table 1).
Received: November 7, 2013
Published: November 27, 2013
© 2013 American Chemical Society
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Letter
a
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Amination of Aryl Chlorides Using LiOtBu
b
b
entry
mol % 2
additive
base
conversion
yield
1
2
3
4
5
none
NaOtBu
KOtBu
LiOtBu
LiOtBu
LiOtBu
NaOtBu
KOtBu
LiOtBu
LiOtBu
LiOtBu
21%
23%
54%
90%
100%
14%
4%
10%
9%
5
none
5
none
49%
86%
91%
5%
5
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
c
5
5
6
7
5
5
<4%
68%
50%
60%
d
8
5
79%
58%
68%
9
2.5
2.5
e
10
a
Reaction conditions: aryl chloride (1.0 mmol), amine (1.5 mmol),
a
Reaction conditions: 3 (0.25 mmol), 4 (0.375 mmol), base (0.375
LiOtBu (1.5 mmol), 2 (5 mol %), dppf (5 mol %), MeCN (1.0
mmol), CPME (2 mL), 100 °C, 1 h. Yields are of the isolated product,
average of two runs. b Reaction time 16 h. c 2 (10 mol %) and dppf (10
mol %), 130 °C, 16 h.
mmol) 2 (2.5−5 mol %), dppf (2.5−5 mol %), additive (0.25 mmol),
b
CPME (0.5 mL), 100 °C, 15 min. Determined by GC using
c
dodecane as the internal standard. Reaction time was 45 min. Isolated
d
yield was 85%, 1 mmol scale, average of two runs. No additional dppf
e
was added. Reaction time was 1 h. CPME = cyclopentyl methyl ether.
ypyrimidine in 82% yield, although the reaction required an
increased catalyst loading and higher temperatures to achieve
full conversion (6d, Scheme 2). The arylation of indoline with
1-chloronaphthalene suffered from significant reduction of the
aryl halide presumably due to competing β-hydride elimination,
but the desired product was still isolated in 60% yield (6e,
Scheme 2).
Although our catalyst system proved to be highly effective for
amination of aryl and heteroaryl chlorides using LiOtBu, we
were interested in expanding the scope of the reaction to
include substrates bearing base-sensitive functional groups. Due
to their lower pKa values relative to alkylamines, we felt that
anilines would be readily deprotonated during the trans-
metalation step (amine binding and deprotonation) under
weakly basic conditions.23 Thus, by changing the solvent to
tBuOH and employing K3PO4 as the base,24 we found that a
wide variety of primary and secondary anilines could be
efficiently arylated (Scheme 3). These conditions were found to
tolerate base-sensitive functional groups as well as ortho-
substitution on the aryl halide and the amine nucleophiles,
including anilines containing an ester substituent in the ortho
position (Scheme 3).
Having established the conditions for the arylation of anilines
using K3PO4, we sought to expand the reaction scope further to
include phenol-derived aryl electrophiles. While the amination
of aryl sulfamate electrophiles is well-established,2c,3d,g the
amination of aryl mesylates with Ni-catalyst systems remains
unknown.25,26 Furthermore, only one successful example of Ni-
catalyzed amination of an aryl triflate has been reported.27 As
aryl mesylate and some aryl triflate electrophiles are known to
be sensitive to strong bases,25a,28 we felt that application of the
developed weak base conditions would enable the successful
amination of these electrophiles. However, the use of tBuOH
proved to be detrimental to the reaction, resulting in modest
yields of the desired product. By using CPME as the solvent
and performing the reaction at a slightly lower concentration a
dramatic improvement of the product yields was observed. As
with the aryl chloride substrates, these conditions were able to
KOtBu as a base provided a similar result (9% yield), while the
use of LiOtBu led to a marked improvement in reactivity, giving
the coupled product (5) in 49% yield (entries 2 and 3, Table
1), demonstrating that the choice of counterion is crucial to the
success of the reaction when using tert-butoxide bases.18
Previously, Hartwig has shown that the addition of benzonitrile
improved the reactivity in Ni-based systems−potentially
stabilizing the catalytically active Ni-species.19 Similarly, we
found that the addition of 1 equiv of acetonitrile greatly
improved the reactivity of 2, producing the product 5 in 86%
yield (entry 4, Table 1). Extending the reaction time to 45 min
gave full conversion of the aryl chloride, and product 5 was
isolated in 85% yield (entry 5, Table 1). The use of the
acetonitrile additive with either NaOtBu or KOtBu, however,
still resulted in low yields (entries 6 and 7, Table 1).
Conducting the reaction without an additional equivalent of
the dppf ligand led to a diminshed yield of 5 (entry 8, Table 1),
and lowering the catalyst loading had a similarly detrimental
effect, with the reaction failing to reach full conversion even
after extended reaction times (entries 9 and 10, Table 1).
In addition to the desired arylamine product 5, a small
amount of the corresponding aminated o-tolyl product (2%)
was also observed. This byproduct is likely the result of catalyst
activation, and similar byproducts have been observed in other
systems using Ni(II)−(σ-aryl) complexes as precatalysts.20,21
We note that the corresponding aminated o-tolyl byproducts
from 2 were not observed in many of the reactions using 2. In
the instances when they were formed, the small amounts (0.5−
5%) were easily separated during purification.22
With the conditions for amination identified, we investigated
the scope of this reaction with aryl and heteroaryl chlorides.
The catalyst system was found to tolerate both cyclic and
acyclic secondary alkylamines, which were coupled in high yield
(6a and 6b, Scheme 2). Primary anilines, including the bulky,
ortho-substituted 2-aminobiphenyl, were readily arylated in
excellent yield (6c and 6f, Scheme 2). Diphenylamine also
underwent facile cross-coupling with 2-chloro-4,6-dimethox-
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Letter
a
array of amine nucleophiles efficiently with aryl and heteroaryl
electrophiles, including substrates containing base-sensitive
functional groups.
Scheme 3. Amination of Aryl Chlorides Using K3PO4
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures along with experimental and spectro-
scopic data for new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: sbuchwal@mit.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
a
Research reported in this publication was supported by the
National Institutes of Health under Award Number GM58160.
The content is solely the responsibility of the authors and does
not necessarily represent the official views of the National
Institutes of Health. N.H.P. acknowledges a National Science
Foundation Graduate Research Fellowship. We thank Dr.
Aaron C. Sather (MIT), Dr. Sean M. Smith (MIT), and
Ekaterina V. Vinogradova (MIT) for aid in the preparation of
this manuscript.
Reaction conditions: aryl chloride (1.0 mmol), amine (1.5 mmol),
K3PO4 (3 mmol), 2 (5 mol %), dppf (5 mol %), MeCN (1.0 mmol),
tBuOH (2 mL), 3 Å MS (300 mg), 110 °C, 16 h. Yields are of the
b
isolated product, average of two runs. In cases where using the
standard conditions do not give full conversion, omission of the 3 Å
MS or using 6 mmol of K3PO4 was found to allow the reaction to
c
reach completion. K3PO4 (6 mmol), dioxane (4 mL).
tolerate base-sensitive functional groups as well as ortho-
substituents on either the electrophile or the nucleophile
(Scheme 4).
In summary, we have developed a highly active, dppf-ligated
nickel precatalyst (2) for use in C−N cross-coupling reactions.
This robust precatalyst can be easily prepared from readily
available Ni(II) sources and is air-stable. Furthermore, this
catalyst system has been demonstrated to cross-couple a wide
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Scheme 4. Amination of Aryl Mesylates, Triflates, and
Sulfamates
a
(6) Bolm has reported the use of Cs2CO3 with Ni(COD)2 and
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See reference 2b.
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a
Reaction conditions: aryl chloride (1.0 mmol), amine (1.5 mmol),
K3PO4 (3 mmol), 2 (5 mol %), dppf (5 mol %), MeCN (1.0 mmol),
CPME (4 mL), 3 Å MS (300 mg), 110 °C, 16 h. Yields are of the
isolated product, average of two runs. In cases where using the
standard conditions do not give full conversion, using 6 mmol of
K3PO4 was found to allow the reaction to reach completion. 2 (2.5
b
c
mol %), dppf (2.5 mol %), 4 h.
(10) Chatt, J.; Shaw, B. L. J. Chem. Soc. 1960, 1718.
222
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(11) Concurrent with the advent of Ni(II)−(σ-aryl) complexes as
precatalysts, the groups of Nolan, Matsubara, and Nicasio have made
excellent use of preligated, air-stable Ni−NHC complexes for use in
C−N cross-coupling and other Ni-catalyzed cross-coupling reactions.
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́
Gonzalez, S.; Stevens, E. D.; Nolan, S. P. Organometallics 2005, 24,
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́
R.; Prieto, A.; Alvarez, E.; Belderrain, T. R.; Nicasio, M. C.
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(12) Chen, C.; Yang, L.-M. J. Org. Chem. 2007, 72, 6324.
(13) This system was also further applied to many C−N cross-
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Li, G.; Yang, L.-M. J. Organomet. Chem. 2011, 696, 2482.
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Y.; Zheng, J. R.; Hu, Q.-S. Adv. Synth. Catal. 2011, 353, 2051. (b) Fan,
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(15) See Supporting Information.
(16) No loss of catalyst activity was observed after seven months.
(17) The bond angles for P1−Ni−Cl (167.1°) and P2−Ni−C
(163.7°) show that the complex is distorted from the expected 180°
for square planar geometry.
(18) A similar observation on the differing effects of the tert-butoxide
bases (LiOtBu, NaOtBu, and KOtBu) on product yield was made by
Lipschutz. See ref 5d.
(19) Ge, S.; Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 16330.
(20) For examples where similar byproducts are formed from
Ni(II)−(σ-aryl) precatalysts, see refs 2a, 2b, 12, and 13.
(21) Yang has reported that the cross-coupling of diphenylamine
with aryl halides using Ni(II)−(σ-aryl) precatalysts did not produce
the corresponding arylated diphenylamine byproduct from catalyst
activation. See ref 5j.
(22) The corresponding aminated o-tolyl products were observed in
the crude reaction mixtures of the following substrates: 6c, 6d, 6f
(Table 1); 7a, 7e (Table 2); and 8a, 8c, 8d, 8e (Table 3).
(23) Meyers, C.; Maes, B. U. W.; Loones, K. T. J.; Bal, G.; Lemier
̀
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However, in certain cases (7a, Scheme 3), their use lead to incomplete
conversion of the aryl electrophile, suggesting the benefical role of
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(27) See ref 2c.
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P.; Buchwald, S. L. J. Org. Chem. 1997, 62, 1264. (b) Louie, J.; Driver,
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223
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