Simple Nickel Salts for the Amination of (Hetero)aryl Bromides and Iodides with Lithium Bis(trimethylsilyl)amide

Article abstract of DOI:10.1021/acs.organomet.8b00567

Recent developments in the chemistry of C-N bond formation and the synthesis of anilines have allowed for the use of first-row transition metals to catalyze these transformations. Much of the progress in this area has been driven by comprehensive screening for privileged/tailored ligands, which can be costly and not readily available in a research laboratory setting. In this communication we report a protocol in which simple nickel salts catalyze the C-N cross-coupling reaction between (hetero)aryl bromides and iodides with lithium bis(trimethylsilyl)amide without the need for any additive ligand. This method is amenable to low nickel catalyst loadings (1%) as well as gram-scale reactions. Because of the good functional group tolerance and compatibility with heterocyclic moieties, this method is useful for academic laboratory settings where access to tailored ligands and noble-metal catalysts could be challenging.

Full text of DOI:10.1021/acs.organomet.8b00567

Communication
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Cite This: Organometallics XXXX, XXX, XXX−XXX
Simple Nickel Salts for the Amination of (Hetero)aryl Bromides and
Iodides with Lithium Bis(trimethylsilyl)amide
Gabriel Espinosa Martinez,† Joseph W. Nugent,† and Alison R. Fout*
School of Chemical Sciences, University of Illinois at UrbanaChampaign, 600 South Mathews Avenue, Urbana, Illinois 61801,
United States
S
* Supporting Information
ABSTRACT: Recent developments in the chemistry of C−N bond
formation and the synthesis of anilines have allowed for the use of
first-row transition metals to catalyze these transformations. Much of
the progress in this area has been driven by comprehensive screening
for privileged/tailored ligands, which can be costly and not readily
available in a research laboratory setting. In this communication we
report a protocol in which simple nickel salts catalyze the C−N
cross-coupling reaction between (hetero)aryl bromides and iodides
with lithium bis(trimethylsilyl)amide without the need for any
additive ligand. This method is amenable to low nickel catalyst loadings (1%) as well as gram-scale reactions. Because of the
good functional group tolerance and compatibility with heterocyclic moieties, this method is useful for academic laboratory
settings where access to tailored ligands and noble-metal catalysts could be challenging.
he monoarylation of ammonia is a challenging trans-
formation that has garnered significant interest because of
2-bromonaphthalene to yield N,N-bis(trimethylsilyl)-
naphthalen-2-amine as the only product (determined by GC-
MS). Encouraged by this result, we screened a series of nickel
compounds (NiCl2, NiBr2, (PPh3)2NiCl2, (PPh3)2NiBr2,
NiCl2py4, (DME)NiCl2, and Ni(COD)2, as well as Ni powder
(Table 1)). Interestingly, all the nickel reagents screened
(except for Ni powder) yielded the cross-coupled product
within 3 h at 100 °C.
T
its highly valuable products.1,2 Since the initial report by
Hartwig and co-workers, which featured a Josiphos palladium
system, ligand choice has influenced many of the advances in
this area.3 Further work by Hartwig and Stradiotto expanded
this cross-coupling to nickel using Josiphos ligand deriva-
tives.4,5 The development of copper systems for the
monoarylation of ammonia has been plagued by harsh reaction
conditions; however, a judicious choice of ligands and
additives has led to improved results.6−8 Despite these and
other important advances,9−16 it remains a difficult challenge
to develop effective first-row transition-metal catalysts for this
coupling reaction.
Intrigued by the competence of NiCl2 in the absence of
ancillary ligands,20 as well as the shorter reaction times
required for the more soluble (PPh3)2NiCl2, we narrowed our
Table 1. Nickel Source Screening
Lithium bis(trimethylsilyl)amide (LiN(SiMe3)2), an easy to
handle ammonia surrogate, has been effective in the formation
of aromatic C−N bonds using palladium.17,18 More recently,
work in our group demonstrated that a simple cobalt catalyst,
(PPh3)3CoCl, could effectively couple LiN(SiMe3)2 with aryl
halides but could not tolerate heterocycles.19 The reactivity of
this cobalt catalyst inspired us to explore this chemistry further
with other simple, earth-abundant metal salts. Herein, we
report the usage of simple nickel salts (NiCl2 and
(PPh3)2NiCl2) in C−N coupling reactions of LiN(SiMe3)2
with (hetero)aryl bromides and iodides to form the
corresponding aniline products. This protocol does not require
the use of privileged ligands or external reductants for catalysis
to occur.
a
entry
[Ni] source
(PPh3)2NiCl2
(PPh3)2NiBr2
NiCl2
NiBr2
NiCl2py4
(DME)NiCl2
Ni(COD)2
Ni powder
(PPh3)2NiN(SiMe3)2
loading (%) time (h) conversion (%)
1
2
3
4
5
6
7
8
9
10
3
1
1
2
2
2
3
3
3
1
<1
>99
>99
>99
>99
>99
>99
>99
<1
1
1
5
5
1
1
1
5
1
>99
With the goal of using simple, commercially available, and
relatively inexpensive nickel compounds, we first probed the
competency of nickel(II) chloride in the cross-coupling of 2-
bromonaphthalene and LiN(SiMe3)2. The reaction (100 °C,
toluene, 5 mol % NiCl2) resulted in the complete conversion of
a
Conversion determined by GC-MS.
Received: August 8, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.8b00567
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Communication
g
investigation to these two metal salts on the basis of
commercial availability and cost. We sought to explore the
capability of these two nickel sources to cross-couple PhX (X =
Br, I) with LiN(SiMe3)2 in toluene at room temperature over a
24 h period (Tables S2 and S3). At 10 mol % loading, NiCl2
showed ∼3% conversion of PhI to PhN(SiMe3)2, while the less
reactive PhBr resulted in no conversion at all. Conversely, at
lower loadings (PPh3)2NiCl2 (5 mol %) completely converted
PhI to PhN(SiMe3)2, and at 10% loading it converted 23% of
PhBr to the expected product. These results, in combination
with the improved performance observed for both NiCl2 and
(PPh3)2NiCl2 at higher temperatures, suggests that the
solubility of the metal salt could be key for the success of
the reaction and demonstrates that aryl iodides are more
reactive than bromides under these conditions.
Scheme 2. Scope of Aryl Bromides and Iodides
The performance of (PPh3)2NiCl2 at even lower loadings
(0.5 and 0.1 mol %) at 100 °C in the gram-scale coupling of 2-
bromonaphthalene with LiN(SiMe3)2 was tested (Scheme 1).
Scheme 1. Gram-Scale and Room-Temperature Reactions of
Aryl Halides
a
b
c
2% catalyst, 4 h. Aryl iodide starting material, 70 °C. 5% catalyst,
d
e
18 h, 3 equiv of LiN(SiMe3)2. 2.5% catalyst, 1,4-dioxane. 1,4-
dioxane. Isolated as the bis(trimethylsilyl)-protected amine. Isolated
f
g
yields are an average of duplicate runs.
at all bromide sites. However, the reaction can be used to
install multiple amine functionalities, as observed by the
formation of 5-(tert-butyl)benzene-1,3-diamine (1e) in good
yields. Electron-withdrawing (1f) and electron-donating
groups (1g,h) were also tolerated under the optimized
conditions. Furthermore, oxygen-, nitrogen-, and sulfur-
containing functionalities (1g−i) were tolerated under these
reaction conditions. Although 4-bromoaniline did not produce
the desired product, the reaction of 4-bromoacetanilide (N-
acyl-protected aniline) proceeded to form N-(4-aminophenyl)-
acetamide (1l) in great yield. The reaction conditions also
tolerated ester (1m) and alkene (1n) functionalities. Addi-
tionally, this amination protocol works in the presence of a
boronate ester functionality (1o), providing orthogonal
reactivity in comparison to palladium-catalyzed methods
which require installation of the amine group prior to the
boronate ester functionality.21
Nitrogen-, oxygen-, and sulfur-containing heterocycles are
ubiquitous in natural products and pharmaceuticals, distin-
guishing them as important moieties to explore.22 The
(hetero)aryl bromides investigated are shown in Scheme 3.
The substrates 2-, 3-, and 4-bromopyridine (2a−c, respec-
tively) were successfully coupled to form the aminopyridine
products, which are of interest because of their promise in
treating neurological disorders.23 Exposing 2-bromo-5-methox-
ypyridine to the coupling conditions yielded the product 5-
alkoxypyridin-2-amine (2d) in good yield. The 5-alkoxypyr-
idin-2-amine functionality, found in an oncologically relevant
a
b
Isolated yield. Conversion determined by GC-MS.
At 0.5 mol % loading, the reaction was complete within 6 h,
while 0.1 mol % loading resulted in 62% conversion of the
starting material in 6 h and complete conversion within 24 h.
Both reactions resulted in the isolation of the desired product
in excellent yields.
Initial exploration of functional group tolerance for the
cross-coupling of aryl bromides and iodides with LiN(SiMe3)2
revealed that (PPh3)2NiCl2 was a superior catalyst to NiCl2 in
terms of both functional group tolerance and reaction time.
For these reasons and its commercial availability, (PPh3)2NiCl2
was used to develop the substrate scope of this reaction
(Scheme 2). At elevated temperatures (100 °C) over the
course of 2 h, the reaction of 1-bromo-4-fluorobenzene and 1-
bromo-4-chlorobenzene yielded 4-fluoroaniline (1a) and 4-
chloroaniline (1b) selectively after workup, leaving both the
fluoride and chloride moieties intact. As observed in the room-
temperature reactions, aryl iodides preferentially couple over
aryl bromides. When 1-bromo-4-iodobenzene was heated to 70
°C, 4-bromoaniline (1c) was formed in excellent yield, leaving
the bromide untouched; this allows iodides to be selectively
functionalized in the presence of bromides. Subjecting 1,3,5-
tribromobenzene to the reaction conditions yielded 3,5-
dibromoaniline (1d), as opposed to uncontrolled amination
B
DOI: 10.1021/acs.organomet.8b00567
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observed within 6 h, whereas (PPh3)2NiCl2 at 5 mol % loading
required ∼24 h (Scheme 1).
Scheme 3. Scope for Heteroaryl Bromides
Additional evidence of Ni(I) involvement was provided by
monitoring the fate of the catalyst upon reaction completion.
Reactions of PhBr with LiN(SiMe3)2, one catalyzed by
(PPh3)2NiCl2 and the other catalyzed by (PPh3)2NiN-
(SiMe3)2, were analyzed by 1H NMR spectroscopy after
1
filtration and removal of volatiles. The H NMR spectra of
both reaction mixtures contained resonances consistent with
the independently prepared (PPh3)2NiN(SiMe3)2 (Figures S5
and S6). This suggests that the Ni(I) species (PPh3)2NiN-
(SiMe3)2 could be involved in catalyzing the reaction and that
(PPh3)2NiCl2 is reduced over the course of the reaction to
form the Ni(I) complex. To ensure that the nickel species
present after catalysis was not an inactive decomposition
product, the isolated residue was added to more substrate and
nucleophile, resulting in coupling to the desired product with
no loss in activity. Moreover, no resonances corresponding to
(PPh3)2NiX2 (X = Cl, Br) were observed in the analyzed
mixtures.
In summary, the method presented can be easily adapted in
academic laboratories, especially if synthetically advanced
ligands and/or palladium sources are not accessible. This
method employs simple and inexpensive nickel sources at low
loadings for the cross-coupling of aryl bromides and iodides
with the ammonia surrogate LiN(SiMe3)2, without the
requirement of ancillary ligands or tailored phosphines. The
more soluble Ni sources ((PPh3)2NiCl2 and (PPh3)2NiN-
(SiMe3)2) are competent catalysts even at room temperature,
making this method amenable to aminating thermally sensitive
substrates. The amination of (hetero)aryl bromides featuring
pyridine, quinoline, benzofuran, and (benzo)thiophene moi-
eties, which are ubiquitous in natural products and
pharmaceuticals, was also achieved with this simple nickel
system.
a
b
c
d
e
1,4-Dioxane. Toluene. 2.2 equiv of LiN(SiMe3). 4 h. Isolated as
f
g
TMS-protected product. 3.3 equiv of LiN(SiMe3)2. Conversion
determined by GC-MS. 3 h. Isolated yields are an average of
duplicate runs.
h
i
c-Met inhibitor, was previously transformed from its bromide
precursor to the amine by employing LiN(SiMe3)2, palladium,
and a tailored phosphine ligand.24 Here we have achieved a
similar transformation with a simple nickel salt and no tailored
ligands. This protocol was also successful with 3-bromoquino-
line (2e) and even 8-bromoquinoline (2f), a substrate not
amenable to nickel photoredox coupling conditions.25 5-
Bromobenzothiophene (2g), 2-bromothiophene (2h), and 5-
bromobenzofuran (2i) were also coupled effectively. The
compatibility of this protocol with heterocyclic functionalities
is exciting for the prospect of its adoption in pharmaceutical
and natural product synthesis.
Because many of the reactions for the substrate scope took
place in toluene at elevated temperatures with an excess of
LiN(SiMe3)2 versus (PPh3)2NiCl2 (1% Ni = 110:1 LiN-
(SiMe3)2:(PPh3)2NiCl2), we also explored the competency of
(PPh3)2NiN(SiMe3)2 to catalyze this reaction. We reasoned
that (PPh3)2NiN(SiMe3)2 could be the active species formed
under these conditions, considering that its synthesis is
achieved in toluene at 80 °C starting from (PPh3)2NiCl2.26
To test its competence, independently prepared (PPh3)2NiN-
(SiMe3)2 was reacted with 2-bromonapththalene and LiN-
(SiMe3)2, resulting in complete conversion within the first 1 h
of the reaction with only the desired product observed by GC-
MS (Table 1). Interested in the increased reaction rate, we
studied the initial rate kinetics for (PPh3)2NiCl2 and
(PPh3)2NiN(SiMe3)2; the initial rate of reaction of coupling
PhBr and LiN(SiMe3)2 revealed an induction period of ∼3 min
for (PPh3)2NiCl2 and less of an induction period for
(PPh3)2NiN(SiMe3)2, consistent with the solution reaching
the final temperature (Figure S4). This finding suggests that
the formation of an active Ni(I) catalyst could be responsible
for the induction period observed when using (PPh3)2NiCl2 as
the catalyst. This is further corroborated by the room-
temperature reaction of PhI with LiN(SiMe3)2. At 5 mol %
loading of (PPh3)2NiN(SiMe3)2, complete conversion was
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.8b00567.
Synthesis, characterization data, and kinetic data (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail for A.R.F.: fout@illinois.edu.
■
ORCID
Alison R. Fout: 0000-0002-4669-5835
Author Contributions
†G.E.M. and J.W.N. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for this work was provided by the University
of Illinois at UrbanaChampaign and the NSF (CHE-
1351961). J.W.N. is thankful for a Robert C. & Carolyn J.
Springborn Fellowship. A.R.F. is an Alfred P. Sloan Research
Fellow and a Camille Dreyfus Teacher-Scholar. The authors
thank Profs. Denmark and Hull, as well as Sam Gockel, for
insightful discussions.
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