A Bicyclic N-Heterocyclic Carbene as a Bulky but Accessible Ligand: Application to the Copper-Catalyzed Borylations of Aryl Halides

Article abstract of DOI:10.1021/acs.joc.5b01721

Imidazol-2-ylidene and imidazolin-2-ylidene are frequently employed as the core structures of N-heterocyclic carbene (NHC) ligands, because these have two nitrogen sites adjacent to carbenic carbons. The electronic and steric effects of N-substituents to a bound metal have been aptly studied, and bulky substituents have commonly been introduced on nitrogen(s). However, too much bulkiness can sometimes result in an ineffectiveness of the hindered substrates. In this study, we thoroughly compared our original bicyclic NHC, which has bulky substituents on its noncarbenic carbons, with ubiquitous NHC ligands to probe its steric properties. A well-defined bicyclic NHC-CuCl complex was successfully synthesized and applied to the copper-catalyzed borylations of aryl halides at ambient temperature. A bicyclic NHC-CuCl proved to be a better catalyst than commonly used NHC ligand-Cu complexes, particularly for sterically hindered substrates, which suggested that the bicyclic NHC ligand offered a bulky but accessible environment to the bound copper.

Full text of DOI:10.1021/acs.joc.5b01721

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Article
A Bicyclic N-heterocyclic Carbene as a Bulky but Accessible Ligand:
Application to the Copper-Catalyzed Borylations of Aryl Halides
Shin Ando, Hirofumi Matsunaga, and Tadao Ishizuka
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01721 • Publication Date (Web): 09 Sep 2015
Downloaded from http://pubs.acs.org on September 9, 2015
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A Bicyclic N-heterocyclic Carbene as a Bulky but Accessible Ligand: Application to the
Copper-Catalyzed Borylations of Aryl Halides
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Shin Ando,* Hirofumi Matsunaga, and Tadao Ishizuka*
Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi Chuo-ku, Kumamoto
8
62-0973, Japan
ando@gpo.kumamoto-u.ac.jp (S.A), tstone@gpo.kumamoto-u.ac.jp (T.I.)
Abstract
Imidazol-2-ylidene and imidazolin-2-ylidene are frequently employed as the core structures
of N-heterocyclic carbene (NHC) ligands, because these have two nitrogen sites adjacent to
carbenic carbons. The electronic and steric effects of N-substituents to a bound metal have
been aptly studied, and bulky substituents have commonly been introduced on nitrogen(s);
however, too much bulkiness can sometimes result in an ineffectiveness of the hindered
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substrates. In this study, we thoroughly compared our original bicyclic NHC, which has
bulky substituents on its non-carbenic carbons, with ubiquitous NHC ligands to probe its
steric properties. A well-defined bicyclic NHC-CuCl complex was successfully synthesized
and applied to the copper-catalyzed borylations of aryl halides at ambient temperature. A
bicyclic NHC-CuCl proved to be a better catalyst than commonly used NHC ligand-Cu
complexes, particularly for sterically hindered substrates, which suggested that the bicyclic
NHC ligand offered a bulky but accessible environment to the bound copper.
Introduction
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Beginning with the isolation of a stable carbene, namely N-heterocyclic carbene
1
(
NHC), by Arduengo and co-workers, the chemistry of carbenes has undergone great
improvement in the area of catalysis. This species is now well-recognized not only as an
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organocatalyst but also as an alternative ligand to phosphines. In the area of ligands for
transition metals, its unique binding nature such as a strong σ-donation to the bound
transition metal, remarkably strong binding toward metals, and stability of a resultant
complex under an oxidative condition has motivated organic chemists and led to extensive
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studies in the development of a considerable number of ligands based on NHC.
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(a)
Substituents on
non-carbenic carbons
Electronic properties were studied.
N
N
N-substituents
Higher influences on an active site.
M
Bulky substituents for more stable
and active catalysts.
(b)
N
N
N
N
dilemma
more stable
less accessible
less stable
more accessible
Figure 1. (a) Effects of substituents on NHC ligands. (b) Dilemma of the bulkiness of
N-substituents.
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Although “abnormal” NHC and “expanded-ring” NHC ligands have also been
explored and show unique features, imidazolium and imidazolinium salts are the most
frequently employed as the core structures of NHC precursors. In addition to their
straightforward syntheses, the two flexible, easily tunable nitrogen sites adjacent to the
carbenic carbon is another reason for their popularity. Structurally, the N-substituents on
these core structures exert much more influence on the environment surrounding the metal
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center than the substituents on non-carbenic carbons (Figure 1a). Synthetic chemists go to
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great lengths to protect active sites such as these in order to prevent a decomposition of the
complex and/or functionalization with Lewis basic functional group(s) in order to construct
a multidentate ligand. In particular, sterically demanding N-substituent(s) are often required
for imidazolinium salts in order to construct a stable metal complex. Furthermore, not only
for NHC, the steric demand of ligands is one of the most important factors affecting the
turnover of transition-metal catalysts, and a more demanding ligand facilitates a reductive
elimination step in most cases. Based on these facts, bulky substituents are generally chosen
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as N-substituent(s). However, NHC ligands with bulky N-substituents sometimes suffer
from steric repulsion (Figure 1b). For example, an IAd ligand worked well for
Suzuki-Miyaura cross-coupling reactions, but o-substituted aryl chlorides or aryl boronic
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acids were not tolerated (Figure 2a). This dilemma makes it problematic to use a NHC
ligand, which is normally useful for the transformations of sterically demanding substrates.
Glorius and co-workers suggested the use of bioxazoline-derived NHC ligands with
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restricted flexibility” as one solution to this dilemma. The IBiox ligands used in their
study worked for coupling reactions between hindered aryl halides and aryl boronic acids to
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give tetraortho-substituted biaryls.
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(
a) Glorius et al.
O
O
N
N
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n
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IAd
IBiox
n = 0, 1, 2, 3, 7,
R
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Cl
+
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R'
R'
IAd
not tolerable
tolerable
IBiox
(b) Organ et al.
R
R
Electoron donativity
R = F < H < OMe
N
N
OMe
Cl
B(OH)2
NHC-Pd
+
MeO
R = F
R = H
53%
72%
R = OMe 83%
Figure 2. (a) Suzuki-Miyaura cross-coupling reactions of sterically hindered substrates
were allowed with IBiox ligands. (b) Electronic effects of the substituents on a
benzimidazolylidene NHC core for Suzuki-Miyaura cross-coupling reactions.
The influence of substituents on non-carbenic carbons has been studied much less
than that on nitrogen due to the lack of a versatile synthetic strategy. The examples are
limited, but one is the electronic effect of substituents on the non-carbenic carbons of
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NHCs. Imidazolium or benzimidazolium salts bearing EWGs such as CN or Cl groups
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and EDGs such as Me, MeO, or Me N groups were synthesized to modify the electronic
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properties, and in fact the electron-donating characteristics of these NHC ligands are
lowered by the introduction of EWGs and heightened by EDGs. Organ and co-workers
found that the reactivity of Pd complexes during Suzuki-Miyaura cross-coupling reactions
could be increased by increasing the electron-donating characteristics of NHC ligands
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(
Figure 2b).
Recently, we designed and synthesized a novel type of meso NHC ligand
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DHASI; 4, 5-(9, 10-dihydroanthraceno)-imidazolin-2-ylidene),
which is an
imidazolin-2-ylidene equipped with a bicyclic architecture on its non-carbenic carbons
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3
(
Figure 3). The bicyclic system in our original core structure rigidly fixes an aromatic ring
toward an active site, and the aromatic ring effectively shields a bound metal. This effective
shield enabled us to isolate a AgCl complex with the least-stable N, N’-dimethylated
variant as a bench-top stable solid. In addition to this stabilization effect, an acceleration of
the reductive elimination was observed during the copper-catalyzed allylic arylation with
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PhMgBr. A CuCl complex with the smallest N, N’-dimethylated bicyclic NHC ligand
showed high regioselectivity (α/γ = 20/80), which indicated that the reductive elimination
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was facilitated by the core structure. The stabilization of a metal complex and the facile
reductive elimination were representative properties of “bulky” ligands, and, importantly,
this characteristic of a bicyclic NHC is given by an N, N’-dimethylated derivative. Despite
these experimental properties, X-ray crystallography showed that the distances between the
bound Ag and the carbons on the bicyclic motif ranged from 5.0 to 5.5 Å. These distances
are arguably long enough to expect the environment surrounding metal to be free from
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excess steric pressure. Additionally, our motif retains two independently tunable sites on
nitrogen, where an additional minimum shield can be set depending on the reaction that is
attempted. We hypothesized that these unique features could provide a chance to develop a
bulky but accessible NHC ligand that would work for a metal-catalyzed transformation on
sterically demanding substrates. Here, we describe the application of our original bicyclic
NHC ligand to a copper-catalyzed borylation of aryl halides at ambient temperature. An
NHC-CuCl complex was synthesized through a modified route for meso bicyclic NHC
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precursors, and its structure was confirmed by X-ray crystallography. A thorough
comparison with common NHC ligands clearly indicated that a bicyclic NHC-CuCl
complex tolerated hindered substrates better than ubiquitous NHC ligands.
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Previous Work
Ar ring is fixed toward an active site.
Me
The Ag complex was isolated as a
bench-top stable solid.
N
N
AgCl
The distances between the carbons on
the bicyclic framework and the silver
ranged from 5.0 to 5.5 Å.
Me
DHASIMe-AgCl complex
Ph
DHASIMe-CuCl
PhMgBr
Ph
Br
Ph
Ph
Ph
w/o ligand
DHASIMe
98
20
2
80
Working hypothesis
Features of Bulky ligands
Stabilization of a metal complex
Rigid shield
(well-defined catalyst)
Facile reductive elimination
N
N
R
R
Bulky but Accessible ligands
would work for hindered substrates
M
X
minimum shield
Keep an active site Accessible
Figure 3. A working hypothesis of this study based on observations from previous work.
Results and Discussion
Syntheses of meso DHASI precursors and complexation with AgCl and CuCl
The present study began with a modification of the synthetic strategy of our first
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report, because the synthetic pathway was intended for the development of a chiral
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13b
ligand. For the syntheses of meso NHC ligands, a simultaneous introduction of both
N-substituents seemed to be a more effective route. To accomplish this, we first prepared a
cis diamine 6 as a key intermediate as follows (Scheme 1). The synthesis started with the
1
6
methanolysis of N, N’-diacetylated bicyclic imidazolidinone 1 to afford free
imidazolidinone 2 in an 88% yield. After the introduction of MPM protection to both N-H
functionalities in a quantitative yield, a reduction of the urea moiety was accomplished
using lithium aluminum hydride to give protected imidazolidine 4 in an 89% yield. MPM
protection was then cleaved by TFA in a 91% yield, and treatment with methanolic HCl at
reflux gave the cis diamine 6 as a dihydrochloride salt. From this key intermediate,
reductive amination with >2.0 equivalents of acetone or cyclohexanone proceeded
smoothly and gave N, N’-dialkylated cis diamines. These alkylated diamines were
somewhat unstable under both neutral and basic conditions, and we used the crude products
directly for cyclization in the presence of NH Cl or NH BF , which gave imidazolinium
4
4
4
salts as NHC precursors (90% for DHASICy•HCl 8, 80% for DHASICy•HBF 9, and 93%
4
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for DHASIiPr•HBF 10). Unfortunately, N, N’-diisopropyl imidazolinium chloride 11 could
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not be obtained by direct cyclization when using NH Cl as an acid. Although the
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diisopropylated imidazolium chloride 11 could be obtained from the corresponding BF salt
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via a simple anion exchange with the use of sat. NH Cl aq., its reproducibility was
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unacceptable. Thus, the imidazolidine ring was re-closed with paraformaldehyde in the
presence of PPTS in an 84% overall yield from cis diamine 6, and then imidazolinium
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chloride 11 was obtained through oxidation with NCS in an 89% yield. From
imidazolinium chloride 11, AgCl complex 12 was synthesized in a 90% yield using Lin’s
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methodology, and the transmetalation to CuCl smoothly proceeded from this AgCl
complex in a 98% yield. It is important to note that the silver complex 12 and copper
complex 13 with DHASIiPr were stable solids under air at r.t., while the 1,3-diisopropyl
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benzimidazol-2-ylidene-CuCl complex could be stored only under an inert atmosphere.
Scheme 1. Syntheses of bicyclic NHC precursors and its CuCl complex.
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R
LAH,
MPM
TFA,
N
N
THF, 50 °C
40 °C
N
R
N
O
8
9%
91%
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MPM
1
: R = Ac
NaH, MeOH,
CH Cl , r.t.
4
2
2
2
: R = H (88%)
NaH, MPMCl,
DMF, 0 to 25 °C,
3: R = MPM (quant.)
O
TMSCl
MeOH, !
6%
, NaBH CN
3
NH
NH
NH
2
EtOH/HOAc, r.t.
N
H
2
9
•2HCl
5
6
(
HCHO) , PPTS
i
Pr
N
H
n
N
toluene, !
NH
N
8
4% for 2 steps
iPr
7
(EtO) CH,
r.t.
3
NCS
NH BF (X = BF4)
or NH Cl (X = Cl),
!
4
4
Cl)
ME,
4
D
=
X
(
Ag O,
iPr
2
R
N
N
CH Cl , r.t.
2
2
N
N
(from 11)
M
X
iPr
R
90%
8
: R = Cy, X = Cl (90%)
: R = Cy, X = BF4 (80%)
12: M = AgCl
13: M = CuCl
CuCl,CH Cl ,
2
2
9
r.t., (98%)
1
0: R = i-Pr, X = BF4 (84%)
11: R = i-Pr, X = Cl (89% from 7)
With the DHASIiPr-CuCl complex 13 in hand, crystallographic analysis was
performed to unambiguously confirm the structure of the complex. A crystal suitable for
X-ray diffraction was grown via the slow vapor diffusion of n-hexane into a solution in
THF at r.t. A thermal ellipsoid representation at the 50% probability level is given in Figure
2
0
4
. In the solid state, DHASIiPr-CuCl complex 13 exists as a monomer, whereas the
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diisopropyl-benzimidazolylidene-CuCl complex exists as a dimer with two copper atoms
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each bridged by two Cl ligands. The distance between the carbenic carbon and the copper
was 1.91 Å, and the distances between the carbons of the bicyclic framework and the
copper ranged from 4.86 to 5.47 Å. The two isopropyl groups of DHASIiPr have an
asymmetric conformation, but the most stable conformation in a solution state must be
1
symmetric, as shown by H NMR spectroscopy. To predict the most stable conformation in
a solution state, we analyzed the nuclear Overhauser effect (NOE) spectra in THF-d , and
8
7.07% of it fell between the methine proton of the isopropyl group and the methine proton
on the bridgehead position of the anthracene moiety (see Supporting Information for other
NOEs observed on this complex). On the other hand, the two methyl groups on the
isopropyl group showed no significant NOE. The two methyl groups of the isopropyl group
tended to face in the direction of the copper chloride while in a solution state at ambient
temperature (Figure 5). A steric repulsion between N-substituents and the bicyclic
framework would restrict the free rotation of the N-substituents and cause this stable
conformation. This phenomenon is similar to the principle of chirality transfer using a
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1,2-diphenylethylenediamine (DPEN) backbone, which is mostly used for construction of
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21
the C symmetry on NHC ligands.
2
Figure 4. ORTEP diagram of DHASIiPr-CuCl 13, thermal ellipsoids are shown at the 50%
probability level. Selected bond length (Å) and angles (deg): Cl(1)–Cu(1), 2.115;
Cu(1)–C(17), 1.906; C(17)–N(1), 1.337; C(17)–N(2), 1.332; Cl(1)–Cu(1)–C(17), 175.91;
Cu(1)–C(17)–N(1), 123.65; Cu(1)–C(17)–N(2), 126.88; N(1)–C(17)–N(2), 109.33.
H
H
N
7
.07% nOe
N
CuCl
H
CH
3
3
H C
no nOe
Figure 5. Representative NOE observed on the NMR spectra in THF-d8.
Application for the copper-catalyzed borylation of aryl halide
Arylboronic acids and their esters are surely important compounds that are stable
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1
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3
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2
2
and versatile nucleophiles for Suzuki-Miyaura cross coupling reactions. The arylboronic
acids and boronate esters normally are synthesized through halogen-metal exchange of
aryl-iodide or -bromide with arylmagnesium or -lithium species and subsequent reactions
with trialkylborates. This method is useful for the preparation of relatively simple boron
compounds on a large scale, but some types of base-sensitive functionalities are
incompatible. Alternatively, transition metal catalyzed borylation has emerged as a more
0
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1
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0
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0
23
powerful and widely applicable methodology. Since Miyaura and co-workers discovered
that Pd is a good catalyst for the borylation of aryl halide with bis(pinacolato)diboron
24
(
B pin ), a number of Pd catalysts have been developed for the conversion of aryl-halide,
2 2
2
5
even aryl chloride in some cases, to the corresponding arylboronic acid or boronate ester.
Because of the high cost of palladium, alternates were broadly sought from more abundant
2
6
27
28
and cheaper metals, and nickel, copper, and recently zinc were found to be good
2
9
candidates. In this field, NHC ligands have been applied as well, but at a less frequent rate
30
than that for the borylation of alkyne and alkene substrates. As far as we could ascertain,
the borylations of aryl-halides have never been catalyzed by NHC-Cu. Lin, Marder and
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co-workers reported the first example of the CuI catalyzed borylation of aryl bromide at
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27b
ambient temperature using n-Bu P as a ligand. In their pioneering work, they described
3
how a NHC-Cu complex, specifically IPr-Cu-OtBu, could catalyze the transformation, but
the conversion was moderate during the reaction, even when aryl iodide was used (Figure
6
). We concluded that this ineffective activity might have been caused by the excess steric
effect of the bulky N-substituents of the IPr ligand and that more accessible ligands would
be preferable. Consequently, we decided to investigate this reaction system using a series of
common NHC ligands and our original bicyclic NHC ligands.
Lin, Marder et al.
X
O
O
O
O
CuI (10 mol%),
O
O
B
B
n-Bu P (10 mol%),
3
B
R
+
tert-BuOK, THF, r.t.
R
X = I or Br
48–92%
iPr
iPr
N
N
iPr
Cu
iPr
t
O Bu
Cat.
I
Bpin
only 18% after 5 h, 55% after 17 h.
Figure 6. Copper-catalyzed borylation of aryl halides, as reported by Lin, Marder and
co-workers.
We screened NHC ligands with the copper-catalyzed borylation of
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3
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5
6
4-bromoanisole, and the results are summarized in Tables 1 and 2. The copper source in
this reaction had no significant effect (see Table S1 in the Supporting Information); thus,
we used CuCl for this screening. The N-alkylated imidazolinylidene-CuCl complexes (L7,
L9, and L11), except for our bicyclic NHC, were not sufficiently stable to isolate and use
as a catalyst. In a comparison with our bicyclic NHC ligands, an in situ generation of NHC
by n-BuLi and a simultaneous trap with CuCl were used for the reactions shown in Table 1.
The results from L3 and L4 indicated that the counter anion affected the conversions;
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
therefore, we used BF as a counter anion for all common NHC, DHASIiPr, and DHASICy
4
precursors (Table 1). For the ligands that can be used to isolate copper chloride complexes
3
1
as stable solids, NHC-CuCl complexes were prepared and used as a catalyst (Table 2).
The resultant NHC-Cu complexes were mixed with the substrate and B pin in THF
2
2
followed by the addition of a solution of KOtBu in THF at ambient temperature. Under
these reaction conditions, we presumed that NHC-Cu species were converted to
32
NHC-Cu-OtBu in situ and worked as an active catalyst.
Common NHC ligands based on imidazolium or imidazolinium salts with N-alkyl
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groups (L6 to L11) catalyzed the borylation and gave us the coupled product in moderate
yields (Table 1). The imidazolium salts with N-tert-butyl groups (L6) or N-cyclohexyl
groups (L8) gave the coupled product in yields similar to the reactions with imidazolinium
salts (L7 and L9 respectively); however, a significant amount (44% with L6 and 32% with
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1
L8) of reduced product, which was anisole in this case, was also observed in the crude H
NMR spectra from the reactions with imidazolium salts. Although the mechanism of this
reduction remains unclear, this reaction was also reported by Lin and Marder. The
N-substituents affected the yield of the coupled product, and cyclohexyl groups were the
best N-substituents. SICy was the best of the common NHC ligands we tested. The bicyclic
1
3a
13a
NHC ligand precursors with N-methyl (L1), benzyl (L2), cyclohexyl (L3 and L4), and
isopropyl (L5) groups were also applied to this reaction system, and, gratifyingly, both
DHASICy (L4) and DHASIiPr (L5) were superior to the common NHC ligands. We chose
DHASIiPr (L5) as the best bicyclic NHC ligand to use in minimizing the N-substituents.
Additionally, we tested the DPEN-derived NHC ligands (L12 and L13) that have two
phenyl groups on non-carbenic carbons. Although this core structure seemed to suppress
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1
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
4
4
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5
5
5
5
5
5
5
5
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the pathway that led to a reduction, the conversions to boronate were only moderate.
Table 1. Ligand screening using NHC-Cu complexes prepared in situ.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Br
O
O
O
O
L(5 mol%), CuCl (5 mol%),
n-BuLi, THF, 0 °C;
O
O
B
B
B
+
tert-BuOK in THF (1.2 eq.),
THF, r.t., 20 h
OMe
OMe
1.2 eq.
DHASI ligands
L1: R = Me, X = Cl
R
L2: R = Bn, X = Cl
L3: R =Cy, X = Cl
L4: R = Cy, X = BF4
L5: R = i-Pr, X = BF4
N
N
R
X
Imidazolylidene
Imidazolinylidene
Ph
Ph
N
N
N
N
N
R
R
R
R
N
X
X
R
R
L6: R = t-Bu, X = BF4 L7: R = t-Bu, X = BF4
L8: R = Cy, X = BF4
X
L
9
:
R
=
C
y
,
X
=
B
F
4
L
1
2
:
R
=
C
y
,
X
=
B
F
4
L10: R = i-Pr, X = BF4 L11: R = i-Pr, X = BF4 L13: R = i-Pr, X = BF4
a
Products ratio in a crude mixture
Entry
ligand
Boronate
13
Anisole
23
26
22
18
13
44
15
32
17
31
28
5
S.M.
64
52
22
12
12
8
1
2
3
4
5
6
7
8
9
L1
L2
22
L3
56
L4
70
L5
75
L6
48
L7
47
38
10
26
32
29
49
44
L8
58
L9
57
1
1
1
0
1
2
L10
L11
L12
L13
37
a
1
43
Calculated using H NMR. Combined
46
yields were >98% in all cases.
13
53
4
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Table 2. Ligand screening using well-defined NHC-CuCl complexes.
Br
O
O
O
O
O
O
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B
B
B
NHC-CuCl (C, 5 mol%)
+
tert-BuOK in THF (1.5 eq.),
THF, r.t., 20 h
OMe
OMe
1.5 eq.
N
N
CuCl
C1: DHASIiPr-CuCl
iPr
iPr
N
N
N
N
Cu
Cl
iPr
Cu
Cl
iPr
C2: IMes-CuCl
C3: IPr-CuCl
C5: SIPr-CuCl
C4: SIMes-CuCl
a
Products ratio in a crude mixture
Entry complex
Boronate
Anisole
11
S.M.
16
1
2
3
4
5
C1
C2
C3
C4
C5
73
15
5
22
63
16
79
9
17
74
3
16
81
a
1
Calculated using H NMR. Combined yields were >98% in all cases. IMes =
1
1
1
,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene;
,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene;
,3-bis(2,4,6-trimethylphenyl)imidazolin-2-ylidene;
IPr
=
=
=
SIMes
SIPr
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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4
4
4
4
4
4
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5
5
5
5
5
5
5
6
1,3-bis(2,6-diisopropylphenyl)imidazolin-2-ylidene.
0
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
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9
0
1
2
3
4
5
6
7
8
9
0
The results summarized in Table 2 are from the reactions catalyzed by isolated
and well-defined NHC-CuCl complexes. The DHASIiPr-CuCl complex (C1) worked as
well as a complex prepared in situ (Entry 1), indicating that the in situ trap method
provided a proper active catalyst. However, CuCl complexes with four commonly used,
commercially available, N-arylated NHC ligands (C2 to C5) were not effective catalysts for
this coupling reaction (Entries 2 to 5), which is consistent with the results reported by Lin
and Marder.
We next optimized the solvent, base, and the amount of B pin and base with use
2
2
of the most active DHASIiPr-CuCl complex as a catalyst (Table 3). The ethereal solvents
were usable for this reaction and methyl tert-butyl ether (MTBE) proved to be the best
(Entries 1 to 4). KOtBu was the only base used in this coupling reaction (Entries 5 to 7).
After 4 h, 1.5 equivalent each of B pin and KOtBu resulted in full conversion, and we
2
2
obtained the coupled product in a 90% yield. It should be noted that the borylation
catalyzed by NHC-CuCl was faster than other copper-catalyzed borylations reported to
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date.
Table 3. Optimization of the reaction condition of borylation catalyzed by
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DHASIiPr-CuCl complex
N
N
Br
CuCl
O
O
O
O
O
O
B
B
B
(5 mol%)
+
tert-BuOK in THF (1.5 eq.),
MTBE, r.t., 4 h
OMe
(
Standard condition)
OMe
1.5 eq.
a
Entry
variation from the
standard conditions
None
Products ratio in a crude mixture
Boronate
Anisole
S.M.
0
b
1
2
3
4
5
6
7
91 (90)
9
13
13
11
8
THF as a solvent
75
trace
80
12
86
9
CH CN as a solvent
3
Et O as a solvent
2
NaOtBu as a base
KOMe as a base
Cs CO as a base
5
87
85
85
9
6
13
2
2
3
a
1
b
Calculated using H NMR. Combined yields were >98% in all cases. The yield is shown
in parentheses.
Finally, we examined the substrate scope of the developed DHASIiPr-CuCl
catalyst (Table 4). The borylation of a wide range of aryl bromide substituted with EWG or
EDG were tolerated, and the corresponding coupled products were obtained in an efficient
manner (Entries 1 to 7). The aryl-iodide reacted much faster than -bromide during the
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
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5
5
5
5
5
5
5
6
reaction on 4-bromo-iodobenzene (Entry 8) in the presence of 1.0 equivalent of B pin and
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
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7
8
9
0
1
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5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
KOtBu, and 4-bromophenyl boronate was exclusively obtained in a 77% yield (93%
conversion) within 1 h. The borylation of 4-bromo-iodobenzene with 2.5 equivalent of
B pin and KOtBu produced the 1,4-bis(boronate) in a 48% yield with 26% of phenyl
2
2
boronate and 6% of 4-bromophenyl boronate (Entry 9). 1-Bromo and 2-bromonaphthalene
were both borylated in 73 and 71% yields respectively (Entries 10 and 11), but
2
-chloronaphthalene resulted in only an 18% yield (Entry 12). Ortho-methyl and methoxy
substrates were also borylated in good yields (Entries 13 and 14). Moreover,
2
1
-bromo-m-xylene reacted smoothly, and boronate was obtained in a 69% yield (Entry 15).
-Bromo-2-fluorobenzene was completely converted, but its yield was only 38% (Entry 16).
The borylation of 9-bromoanthracene was somewhat less efficient (48% yield, fully
converted only at 50 °C) compared with other substrates, and anthracene was isolated in a
33% yield as a major byproduct (Entry 17).
33
The SICy-CuCl prepared in situ was applied to the same reaction using
ortho-substituted products to prove our concept. The borylation of 9-bromoanthracene
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catalyzed by SICy-Cu yielded 39% of boronate and 58% of anthracene (Entry 17).
Although 2-bromotoluene (Entry 14) was converted to the corresponding boronate in a
10
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13
14
15
16
17
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32
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36
37
38
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44
45
46
47
48
49
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6
9% yield using SICy-CuCl, the borylation of 2-bromoanisole and 2-bromo-m-xylene with
SICy-CuCl did not proceed, and only a trace amount (less than 5%) of boronate was
1
observed in the H NMR spectra of the crude mixtures (Entries 13 and 15). These results
strongly suggested that the minimum shield of N-substituents on the bicyclic NHC
generated a more accessible environment surrounding the bound copper by comparison
with the use of a SICy ligand.
Although the borylation catalyzed by NHC-Cu showed a broad substrate scope,
there were some limitations. Even with DHASIiPr-CuCl, unfortunately, the most hindered
1
,3,5-triisopropyl-2-bromobenzene gave a 3:2 mixture of a reduced product and the
recovered starting material (Entry 18). Also, heteroaryl halides such as thiophene, quinoline,
and isooxazole were not compatible under the conditions presented in this study.
Table 4. Substrate scope of the borylation of aryl halide catalyzed by the
DHASIiPr-CuCl complex at ambient temperature
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1
1
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1
2
2
2
2
2
2
2
2
2
2
3
3
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3
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X
O
O
O
O
O
O
B
B
NHC-CuCl (5 mol%)
B
R
+
tert-BuOK in THF (1.5 eq.),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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9
0
1
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
MTBE, r.t., time
R
X = Br or I
1.5 eq.
N
N
N
N
Cu
Cl
CuCl
DHASIiPr-CuCl
well-defined)
SICy-CuCl
(prepared in situ)
(
Yield (%)
DHASIiPr-CuCl
Entry Substrates
SICy-CuCl
time (h)
1
2
3
4
5
6
7
8
9
1
PhBr
4-MeOC H Br
71
90
80
68
87
63
63
77
48
73
71
18
70
91
69
3.0
4.0
4.0
4.0
1.5
4.0
4.0
1.0
7.0
4.0
4.0
6.0
6.0
6.0
7.0
5.0
4.0
7.0
56
6
4
4-MeC H Br
6
4
4-PhC H Br
6
4
4-Me NC H Br
2
6
4
4-FC H Br
6
4
3-FC H Br
6
4
a
b
4-BrC H I
6
4
4-BrC H I
6
4
0
1-bromonaphthalene
2-bromonaphthalene
2-chloronaphthalene
2-MeOC H Br
11
c
1
1
2
3
trace
69
6
4
14
2-MeC H Br
6 4
1
1
1
5
6
7
2,6-Me C H Br
trace
2
6
3
2-FC H Br
38
6
4
d
9-bromoanthracene
48
39
e
18
2,4,6-iPr C H Br
N.D.
3
6
2
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a
b
c
1.0 eq. of B pin and KOtBu were used. 2.5 eq. of B pin and KOtBu were used. The
2
2
2
2
10
11
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59
60
d
reaction at 50 °C in the presence of n-Bu NI did not change the yield. The reaction was
4
performed at 50 °C. The reaction at room temperature gave the boronate in a 41% yield
e
with 24% of the recovered starting material. The reduced product was observed in the
1
crude H NMR spectra (reduced product : S.M. = 3 : 2).
Conclusion
In conclusion, we synthesized a bicyclic NHC-CuCl complex via a modified
synthetic route, and successfully applied this complex to the borylation of aryl halides. The
synthesized DHASIiPr-CuCl complex was analyzed by X-ray crystallography, which
showed that the distances between the carbons of the bicyclic framework and the copper
were longer than 4.86 Å. NMR experiments indicated that the bicyclic framework likely
limited the rotation of the isopropyl groups, and resulted in the methyl groups of the
isopropyl faced in the direction of the bound copper in a solution state. Compared with the
copper-catalyzed borylation of aryl halide, the SICy ligand showed the highest activity
among the common NHC ligands we tested, and our original DHASIiPr was superior to the
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
4
4
4
4
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4
4
4
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5
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5
5
5
5
5
5
5
6
common NHC ligands. In particular, the DHASIiPr ligand was amenable to the borylation
of the hindered substrates, suggesting that the bicyclic framework was bulky but accessible.
Additions to the steric effects of N-substituents have been extensively studied, and we
established that a change in the sterics on the non-carbenic carbons of the common NHC
core structure could be added as an optional strategy for tuning the environment of NHC
ligands. Further investigations into the development of DHASI ligands with stable
metal-complexes that show unique activity are being conducted in our laboratory.
Experimental Section
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
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9
0
1
2
3
4
5
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8
9
0
1
2
3
4
5
6
7
8
9
0
General Procedure and Chemicals. All reactions were carried out under an argon
atmosphere with freshly distilled solvents under anhydrous conditions, unless otherwise
2 2
noted. Anhydrous MTBE, CH Cl , and THF were purchased and used without further
distillation. Dimethoxyethane (DME) was distilled from Na. Bis(pinacolato)diboron
2 2
(B pin ) was recrystallized from n-hexane prior to use. 9-Bromoanthracene was
recrystallized from EtOH prior to use. Other reagents were used without further purification.
IMes•HCl, IPr•HCl, SIMes•HCl and SIPr•HCl were purchased and used as received. Other
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common NHC ligand precursors were synthesized according to the literature procedures.
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1
,2-Diphenylethylenediamine (DPEN)-derived NHCs were synthesized according to the
3
5
1
literature procedures. Yields refer to chromatographically and spectroscopically ( H
1
13
NMR) homogeneous materials, unless otherwise stated. H and C NMR spectra were
recorded at 600 and 151 MHz, respectively. Chemical shifts are reported in δ ppm
referenced to an internal tetramethylsilane or solvent peaks. HRMS spectra were obtained
by electrospray ionization (ESI) time-of-flight (TOF) or fast atomic bombardment (FAB)
mass spectrometry.
N,
N’-dihydro-Imidazolidinone
2:
2
,6
meso-3,5-diazadibenzo[h,k]tricyclo[5.2.2.2. ]undeca-8,10-dien-4-one. MeOH (20 mL)
2 2
and CH Cl (20 mL) were added to a flask charged with N,N’-diacetylimidazolidinone 1:
2
,6
meso-3,5-diacetyl-3,5-diazadibenzo[h,k]tricyclo[5.2.2.2. ]undeca-8,10-dien-4-one (3.46 g,
10.0 mmol) and a magnetic stir bar at 25 °C. After cooling to 0 °C in an ice bath, NaH
(60% in mineral oil, 200 mg, 5.0 mmol) was added to the resulting solution, and the
2
reaction mixture was stirred at 25 °C for 1 h. H O (100 mL) was then added to the resulting
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2
2
2
2
2
2
2
2
2
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4
4
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4
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5
5
5
5
5
5
5
6
2
mixture at 0 °C, and the off-white solid precipitated was filtered and washed with Et O (×
0
1
2
3
4
5
6
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8
9
0
1
2
3
4
5
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7
8
9
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1
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9
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9
0
1
2
3
4
5
6
7
8
9
0
2
2 2
) and CH Cl (× 3). The resulting solid was dried under reduced pressure to afford the
1
titled compound 2 (2.31 g, 88%) as an off-white powder. m.p. 278–280 °C (decomp.); H
6
NMR (600 MHz, DMSO-d , 298 K): δ = 7.35 (dd, J = 5.4, 3.0 Hz, 2H), 7.26 (dd, J = 5.4,
3
.0 Hz, 2H), 7.13 (dd, J = 5.4, 3.0 Hz, 4H), 6.29 (s, 2H), 4.37 (s, 2H), 3.89 (s, 2H) ppm;
1
3
1
6
C{ H} NMR (151 MHz, DMSO-d , 298 K): δ = 161.8, 140.8, 139.6, 126.2, 126.1, 125.7,
1
24.6, 55.1, 48.8 ppm; IR (KBr pellet): νmax = 3191, 3074, 2932, 2904, 1703 (C=O), 1466,
-
1
1459, 1341, 1311, 1205, 1268, 1226, 1146, 1045, 938, 807, 743 cm ; HRMS (ESI+): m/z
+
calcd. for C17
H
14
N
2
ONa [M+Na] : 285.1004; found: 285.0985.
N,
N’-bis(4-methoxybenzyl)-imidazolidinone
3:
2
,6
meso-3,5-bis(4-methoxyphenylmethyl)-3,5-diazadibenzo[h,k]tricyclo[5.2.2.2. ]undeca
-
8,10-dien-4-one. DMF (50 mL) was added to a flask charged with compound 2:
2
,6
meso-3,5-diazadibenzo[h,k]tricyclo[5.2.2.2. ]undeca-8,10-dien-4-one (2.62 g, 10 mmol),
4
-methoxybenzyl chloride (3.26 mL, 24.0 mmol) and a magnetic stir bar at 25 °C. The
solution was then cooled to 0 °C in an ice bath, and NaH (60% in mineral oil, 963 mg, 24
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mmol) was added to the resulting solution. After stirring for 30 min at 0 °C, the reaction
mixture was warmed to 25 °C and stirred for 2 h at the same temperature. The reaction was
then quenched with MeOH (2 mL) at 0 °C, and the resulting solution was stirred for 30 min
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4 2
at 25 °C. Sat. NH Cl aq. (5.0 mL) and H O (40 mL) were added to this solution at 0 °C, and
2
the crude solid precipitated was filtered and washed with H O (× 2) and then n-hexane (×
2 2 2 4
2). The washed solid was dissolved in CH Cl , and the solution was dried over Na SO ,
filtered, and concentrated under reduced pressure. The crude residue was recrystallized
2 2
from CH Cl /n-hexane, and its mother liquor was concentrated under reduced pressure
(3.95 g of pure titled compound was obtained from this process as a colorless crystalline).
The crude residue was purified by flash column chromatography (30 to 50%
EtOAc/n-hexane) on silica gel (50 mL) to afford the titled compound 3 (1.24 g, total yield
f
was quantitative) as a colorless solid. R = 0.36 (50% EtOAc/n-hexane); m.p. 179–180 °C;
1
3
H NMR (600 MHz, CDCl , 298 K): δ = 7.25 (d, J = 8.4 Hz, 4H), 7.17 (dd, J = 5.4, 3.0 Hz,
2
H), 7.08 (dd, J = 5.4, 3.0 Hz, 2H), 7.06 (dd, J = 5.4, 3.0 Hz, 2H), 7.02 (dd, J = 5.4, 3.0 Hz,
2H), 6.89 (d, J = 8.4 Hz, 4H), 4.57 (d, JAB = 15.0 Hz, 2H), 4.37 (s, 2H), 4.10 (d, JAB = 15.0
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