Copper-Mediated C-N Coupling of Arylsilanes with Nitrogen Nucleophiles

Article abstract of DOI:10.1021/acs.orglett.6b02543

A method for the oxidative coupling of arylsilanes with nitrogen nucleophiles is reported. This method occurs with a broad range of heptamethyltrisiloxylarenes and nitrogen nucleophiles, proceeds with the arylsilane as limiting reagent, and does not require a fluoride activator with electron-poor arylsilanes. The combination of this method with C-H silylation generates arylamines from unactivated arenes with site selectivity controlled by steric effects. This combination of steps gives direct access to many compounds that cannot be accessed via alternative C-H functionalization methods, including direct C-H amination or the combination of C-H borylation and amination.

Full text of DOI:10.1021/acs.orglett.6b02543

Letter
pubs.acs.org/OrgLett
Copper-Mediated C−N Coupling of Arylsilanes with Nitrogen
Nucleophiles
Johannes Morstein, Eric D. Kalkman, Chen Cheng, and John F. Hartwig*
Department of Chemistry, University of California, Berkeley, California 94720, United States
S
* Supporting Information
ABSTRACT: A method for the oxidative coupling of arylsilanes
with nitrogen nucleophiles is reported. This method occurs with a
broad range of heptamethyltrisiloxylarenes and nitrogen nucleo-
philes, proceeds with the arylsilane as limiting reagent, and does not
require a fluoride activator with electron-poor arylsilanes. The
combination of this method with C−H silylation generates
arylamines from unactivated arenes with site selectivity controlled
by steric effects. This combination of steps gives direct access to many compounds that cannot be accessed via alternative C−H
functionalization methods, including direct C−H amination or the combination of C−H borylation and amination.
harmaceuticals, agrochemicals, and natural products often
Pcontain arylamine units or derivatives of arylamines (Figure
1). The C−N bonds in these molecules are frequently
constructed through transition metal-catalyzed amination of
functionalized arenes, including Pd-catalyzed coupling of aryl
halides with nitrogen nucleophiles1 or Cu-mediated oxidative
coupling of arylboronic acids with nitrogen nucleophiles.2 These
methods are reliable and tolerate a broad scope of reagents.
However, the substitution pattern of the arenes is intrinsically
limited by the regioselectivity of the halogenation of arenes to
prepare the electrophilic partner in cross-coupling to form C−N
bonds or to prepare the arylboronic acids used in oxidative
coupling.
method for the amination of functionalized arenes to form
products possessing substitution patterns different from those
created by electrophilic aromatic substitutions would comple-
ment the arylamine derivatives generated by the aforementioned
methods.
Arylboronates can be conveniently accessed by transition-
metal catalyzed C−H-borylation with sterically controlled
regioselectivity and are therefore attractive alternative substrates
for oxidative coupling with nitrogen nucleophiles. However, in
published procedures, the yields of coupling of nitrogen
nucleophiles with arylboronate esters that can be accessed by
C−H-borylation are moderate.4 Recently, a modification of the
coupling of arylboronates with nitrogen nucleophiles with good
yields of arylamines was reported (average yield = 65%).5
However, the reported scope of nucleophiles is limited to aryl-
and alkylamines as nitrogen nucleophiles and uses different
conditions for the coupling of arylamines and alkylamines.
Organosilanes are attractive alternatives to arylboronates.6
The catalytic silylation of aryl C−H bonds forms arylsilanes with
regioselectivities that are higher than, and in some cases distinct
from those of C−H borylation.6a,7 Moreover, arylsilanes are
inexpensive, nontoxic,8 and more stable9 than their arylboronate
analogues. The greater stability of arylsilanes than of
arylboronates and the greater selectivity of C−H silylation than
of C−H borylation creates the capability to functionalize
heteroarenes and complex molecules that cannot be function-
alized by C−H borylation.
Figure 1. Biologically active molecules, which can be conveniently
synthesized by coupling of a prefunctionalized arene with an N-
nucleophile.2d
Undirected, intermolecular amination of the C−H bonds in
arenes is an alternative to more common aminations of
prefunctionalized arenes (Figure 1).3 Recent methods reported
by Nicewicz3b and Falck3c generate arylamines directly from
simple arenes with the arene as limiting reagent. However, these
methods occur with a limited range of nitrogen nucleophiles,
with limited compatibility of auxiliary functional groups, and only
with arenes that are electron-rich. Moreover, the regioselectiv-
ities of these methods are controlled by the electronic properties
of the arene (ortho/para to electron-donating substituents). A
Initial studies by Lam demonstrated that phenyltrimethox-
ysilanes undergo Cu-mediated oxidative amination with five
different nitrogen nucleophiles with TBAF as a fluoride
additive.10 Although these reactions showed that arylsilanes
could be converted to arylamines, the aryltrimethoxysilanes used
in this process have not been accessed by C−H silylation.
Received: August 25, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02543
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Organic Letters
Letter
a
Scheme 1. Scope of the Coupling of Nitrogen Compounds with 1
a
Reaction conditions: 1 (0.3 mmol), 2b−p (0.6 mmol), Cu(OAc)2 (0.9 mmol), Na2CO3 (0.6 mmol), NaF (0.6 mmol), and dry DMSO (2.0 mL).
b
Air atmosphere, heated at 80 °C for 16 h. Yields are isolated yields and yields in parentheses are yields by NMR. Reactions conducted in the
absence of a fluoride source.
Aryltrimethoxysilanes are typically prepared from aryl halides;
thus, this amination does not significantly expand the scope of
substituted arenes that undergo oxidative amination beyond
those of typical arylboronic acids. Moreover, the reported
method requires an excess (2 equiv) of the arylsilane, and the
arylsilane is often the more valuable component of the coupling
reaction. A catalytic amination of arylsilanes was also reported,11
but the high cost of the phosphine ligand [(C6F5)3P] and high
ligand loading (10%) as well as the limited scope of arylsilanes
that underwent this reaction make it unclear if the existing
method could be made more broadly applicable.10−12
Because of the potential of arylsilanes derived from C−H bond
functionalization to serve as intermediates for the synthesis of
arylamines, we sought a practical method for the oxidative
amination of heptamethyltrisiloxylarenes (HMTS-arenes),
which are readily accessible by C−H silylation. Herein, we
report the coupling of HMTS-arenes with nitrogen nucleophiles
that occurs with broad scope of the nitrogen nucleophiles and
arylsilanes and is the first amination of arylsilanes with the
arylsilane as limiting reagent. Reactions without a fluoride
additive give the arylamine products in yields that are similar to
those with a fluoride additive, thereby overcoming one of the
major limitations of the functionalization of arylsilanes.9b
Our initial studies to develop the oxidative coupling of
arylsilanes with nitrogen nucleophiles were guided by several
features of the mechanism of Chan-Lam type coupling.13
Mechanistic studies have shown that transmetalation of the
aryl group from the boronate to Cu(II) is the rate-limiting step of
the common Chan-Lam reactions of arylboron derivatives.14 In
general, transmetalation of an organic group from silicon to a
transition metal is slower than transmetalation from boron to a
transition metal. Thus, our studies focused on identifying
conditions that could facilitate transfer of the aryl group from
the silane to copper. We reasoned that the polarity of the solvent
and the additives that can mediate transfer of the aryl group by
creating a hypervalent silicon derivative or a bridge to the
transition metal15 could be critical factors to increase the rates of
transmetalation.
We selected arylsilane 1 as the substrate for our initial
evaluation of conditions because this compound can be formed
easily by the silylation of 1,3-dichlorobenzene on a 20 mmol
(3.0 g) scale. Moreover, we considered that 1 was likely to be one
of the least reactive arylsilanes because it is electron deficient.16
Testing a series of additives to activate the silane (entry 2−7)
revealed that the ratio of diarylamine product 3a to
homocoupling product 6 is strongly dependent on the identity
of the activator. Reactions conducted with TBAF, which is a
typical activator for the coupling of 2 with aryltrimethoxysilanes,
gave the coupled, diarylamine product 3a in only a modest yield
(26%). This reaction, as well as reactions with CsF, formed
significant amounts of product from homocoupling of the
arylsilane (53−70%). Reactions conducted with fluoride sources
that are less activating than CsF predominantly formed 3a. The
highest yield (79%) was obtained with NaF (entry 3).
The amount of the two minor side products (arene from
desilylation and phenol from oxidation) was higher at 100 °C
(entry 12) than at 80 °C, resulting in a lower yield (61%) of 3a at
this higher temperature than was observed at 80 °C (84%) (entry
11).17
Further evaluation of the reaction conditions showed that
stoichiometric amounts of copper are required (entry 9).
However, the yields of 3a from the reaction with equimolar
amounts of copper and 1 were similar to those with excess copper
(3 equiv) (78% vs 79%). We decided to explore this reaction with
excess copper further because the yield of 3a was slightly higher
under these conditions, and the price of anhydrous copper
acetate (about $1/gram, or $0.18/mmol) is negligible for
reactions on laboratory scale. The highest yields of 3a were
obtained with a 2-fold excess of aniline at 80 °C with Na2CO3 as
the base (entry 10).
The scope of nitrogen nucleophiles that couple with 1 is
shown in Scheme 1. Anilines containing a range of functional
groups and substitution patterns gave the arylamine products in
B
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Organic Letters
Letter
a
Scheme 2. Scope of the Coupling of Arylsilanes with N-Nucleophiles
a
Reaction conditions: 4a−i (0.3 mmol), N-nucleophile (0.6 mmol), Cu(OAc)2 (0.9 mmol), Na2CO3 (0.6 mmol), NaF (0.6 mmol), and dry DMSO
b
(2.0 mL). Air atmosphere, heated at 80 °C for 16 h. Yields are isolated yields, and yields in parentheses are yields by NMR. Reactions conducted in
the absence of a fluoride source. KHF2 was used as fluoride source. Reaction was conducted at 100 °C for 2 d.
c
d
high yields (3b−d). The reaction of a diarylamine (2e) also gave
the triarylamine product, although the yield for this reaction was
lower than that for the reaction of the primary arylamines.
Reactions of aminopyridines (2f), - pyrimidines (2g), -pyrazines
(2h), -pyrazoles (2i), and -thiophenes (2j) also led to the
coupled products in good to excellent yields. Furthermore,
pyrrole 2k coupled directly with 1.
The reaction also occurred at the N−H bond of a series of
amides (2l−m) and sulfonamides (2n). In previous studies,
amides reacted with phenyltrimethoxysilane to give only
moderate yields of the coupled product.10−12,18
those of the amination products from the C−N couplings of
electron-poor substrates. We reasoned that a more activating
fluoride source could facilitate conversion of the electron-rich
substrates 4h and 4i and therefore tested KHF2 as activator.
These reactions formed 5h in a moderate yield (37%) and 5i in a
low yield (14%) after 16 h.
The fluoride additive in the functionalizations of arylsilanes
can deter the use of these reactions in some settings and scales.
The need to activate the silicon reagents with a fluoride has been
addressed by Denmark and co-workers, who developed
protocols for cross-coupling to form C−C bonds that do not
require fluorides.9b However, arylsilanes have not been shown to
undergo coupling with nitrogen nucleophiles without a fluoride
additive. Our initial evaluation of conditions for the results of
Schemes 1 and 2 revealed that the reaction of 1 with 2 at 65 °C
proceeded without a fluoride source (Table 1; entry 1), but the
yield of arylamine from the reaction without fluoride was lower
than that from the reaction with NaF (57% vs 79%).
Comparison of the reaction profile of the reaction without
NaF with that of the reaction with NaF revealed that the reaction
proceeds faster in the presence of NaF, most likely due to
acceleration of the transmetalation step (see the Supporting
Information). On the basis of this observation, we investigated
opportunities for a fluoride-free reaction variant and ran
reactions with representative amines (3b,c,e,f,h,i,j,l,m,o,p) and
HMTS-arenes and heteroarylsilanes (5a,b,c,d,f,j) at 80 °C in the
absence of a fluoride source. Because of acceleration of the
reaction at this temperature, the yields of coupled products
without fluoride were similar to those of reactions with NaF
(Schemes 1 and 2). Electron-rich arylsilanes still require a
fluoride additive to generate the product in acceptable yields.
In conclusion, we developed a method for the coupling of
HMTS-arenes with a wide range of nitrogen nucleophiles to
form the C−N bond in arylamines and their derivatives. This
process, in combination with the silylation of C−H bonds, gives
access to a broad scope arylamines directly from unactivated
arenes and heteroarenes. Unlike other methods for coupling of
arylsilanes to form C−N bonds, this method proceeds with the
arylsilane as limiting reagent. This stoichiometry is valuable
because the arylsilanes obtained from C−H silylation are often
Aliphatic amines (2o−p) also coupled with the arylsilane,
although in lower yields than the reactions of less basic nitrogen
nucleophiles. During the reaction with aliphatic amines, a change
of color from green blue to deep blue was observed upon the
addition of the amine. This change in color suggests that the
amine coordinated to the copper. This coordination could
interfere with the transmetalation of the aryl group from Si to Cu
and cause the yields for reactions of alkylamines to be
moderate.14 The robustness of the presented method was
demonstrated by running a gram-scale reaction with a yield of
1.19 g (76%) of 3m.
The scope of arylsilanes that undergo this process is shown in
Scheme 2. For these studies, 2-pyrrolidone was used as the
nucleophile because copper-catalyzed oxidative couplings of
lactams have been used extensively for the synthesis of PPAR
agonists,19 and the yield of 3m (77%) is in the middle of the
range of yields from reactions of the various nitrogen
nucleophiles (Scheme 1). The results in Scheme 2 show that
the conditions we developed for the coupling of the
3,5‑dichlorophenylsilane are suitable for the coupling of a
broad array of arylsilanes. Substrates containing halide, ester,
trifluoromethyl, ether, sulfonyl, cyano, and amide functional
groups (4a−e) gave the coupled products in good yields. In
addition to arylsilanes, heteroarylsilanes, such as silylpyrimidines
(4j), underwent coupling with 2f under the conditions we
developed.20 Thus, the reported method gives access to
arylamines, such as 5f and 5j, from substrates that are inaccessible
through C−H borylation.7 The yield of 5h under the reported
condition was lower (8% yield by NMR spectroscopy) than
C
DOI: 10.1021/acs.orglett.6b02543
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Organic Letters
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Table 1. Evaluation of Conditions for the Cu-Mediated
Coupling of 1 with 2
ACKNOWLEDGMENTS
■
a
We thank the NIH (GM-115812) for support of this work. J.M.
thanks the German National Academic Foundation (Studien-
stiftung) for supporting his research in the Hartwig lab.
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2 (2.0 equiv), 80 °C
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ASSOCIATED CONTENT
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S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02543.
Detailed experimental procedures and characterization of
products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jhartwig@berkeley.edu.
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.6b02543
Org. Lett. XXXX, XXX, XXX−XXX