Synthesis of chiral C1-symmetric N-heterocyclic carbene ligands: Application toward copper-catalyzed homocoupling of 2-naphthols

Article abstract of DOI:10.1055/s-0033-1338564

Novel chiral C ₁-symmetric NHC ligands can be prepared via dialkylation of chiral imidazoline scaffolds. Asymmetry in the ligand/metal complexes results from a chiral relay effect. The C ₁-symmetric nature of the NHC ligand was proposed to allow for improved reactivity versus other achiral and chiral NHC complexes. The benefit of such ligands was demonstrated in copper-catalyzed oxidative coupling reactions. Georg Thieme Verlag KG Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1338564

PAPER
▌375
paper
Synthesis of Chiral C1-Symmetric N-Heterocyclic Carbene Ligands: Applica-
tion toward Copper-Catalyzed Homocoupling of 2-Naphthols
Chiral C1-Symmetric N-Heterocyclic Carbene Ligands
Michael Holtz-Mulholland, Shawn K. Collins*
Département de Chimie, Centre for Green Chemistry and Catalysis, Université de Montréal, CP 6128 Station Downtown, Montréal, QC, H3C
3J7, Canada
Fax +1(514)3437586; E-mail: shawn.collins@umontreal.ca
Received: 13.08.2013; Accepted after revision: 30.10.2013
One of the alkylations would have to install a relatively
Abstract: Novel chiral C1-symmetric NHC ligands can be prepared
bulky substituent that would help define an eventual
via dialkylation of chiral imidazoline scaffolds. Asymmetry in the
asymmetric environment around the metal through a chi-
ligand/metal complexes results from a chiral relay effect. The C1-
symmetric nature of the NHC ligand was proposed to allow for im-
ral relay effect (Figure 1).8 A second alkylation of the im-
proved reactivity versus other achiral and chiral NHC complexes. idazoline motif would allow introduction of a substituent
The benefit of such ligands was demonstrated in copper-catalyzed
oxidative coupling reactions.
that could act to control the reactivity of the eventual met-
al complex. NHC ligands bearing combinations of bulky
Key words: oxidative coupling, binaphthols, N-heterocyclic car-
benes, copper, catalysis
and small N-substituents have been previously exploited
in asymmetric catalysis,3,9 and served as inspiration for
the development of a simple route to new ligands having
similar steric properties.
N-Heterocyclic carbenes (NHC) have had a tremendous
impact in organic synthesis, both as organocatalysts and
as ligands in transition-metal-based catalysis.1 The impact
of steric and electronic modifications of the carbene li-
gands upon their respective metal complexes continues to
be an area of intense investigation. Recently, a number of
asymmetric transformations catalyzed by chiral NHC
complexes have appeared in the literature.2 In general,
NHC ligands having C2 symmetry have garnered the most
attention, most likely due to the ease of synthesis. Howev-
er, recently greater attention has been given to NHC li-
gands which have a C1-symmetric substitution pattern,
despite the more laborious synthesis required. For exam-
ple, copper complexes bearing C1-symmetric NHC li-
gands have been found to afford ideal steric environments
about the copper center,3 allowing for a fine-tuning of
both the reactivity and enantioselectivity of their respec-
tive processes.4,5 In the majority of the studies reported,
the optimization of the ligand structure could be tedious
and time consuming. As such, new methods to rapidly af-
ford NHC ligands for asymmetric catalysis are required.
R3
R3
R3
R3
R3
R3
sequential
alkylations
N
N
R2
R1
N
N
N
HN
R2
R1
M
X
X
R1 = bulky substituent to control asymmetry about the metal center
2 = small substituent to attenuate complex reactivity
3 = large groups to enforce a chiral relay towards the metal center
R
R
Figure 1 Rapid synthesis of chiral C1-symmetric NHC ligands via
dialkylation of a key imidazoline fragment
For introduction of a bulky substituent (R1, Figure 1) that
could be easily installed via alkylation, a series of diaryl-
methanes were investigated (Table 1). A bis(2-tolyl)meth-
ane group, previously utilized on a NHC–Cu complex to
extend a chiral environment about a copper center,10 was
initially explored. Upon treatment of the imidazoline 1
with strong bases such as sodium hydride or butyllithium
in tetrahydrofuran and subsequent treatment with diaryl-
methane 2a, none of the desired product 3a was isolated.
However, refluxing the imidazoline 1 and the bromide 2a
together in acetone in the presence of potassium carbonate
for one day afforded the N-substituted imidazoline 3a in
30% isolated yield. Adding sodium iodide as an additive
and extending the reaction time to two days afforded a
slight increase in the yield of 3a to 35%. Heating the mix-
ture to 100 °C in a sealed tube over two days afforded the
optimal yield of 45%. The addition of sodium iodide or
other silver-based additives did not improve the yield. The
challenging alkylation is thought to be due to the bulky
tert-butyl groups found along the imidazoline skeleton.
However, with optimized conditions in hand, it was found
that other diarylmethanes could be used to alkylate 1 (Ta-
ble 1, entries 2–5). The mesityl-derived alkyl chloride 2b
Herein, we report a simple dialkylation protocol for the
generation of C1-symmetric NHC ligands. Our prelimi-
nary findings demonstrate the applicability of the NHC li-
gands in forming NHC–Cu complexes for use in the
oxidative homocoupling of 2-naphthols.6
Our initial ligand design for the rapid generation of chiral
C1-symmetric NHC ligands consisted of exploiting the
chiral imidazoline 1, available on a gram scale via a four-
step procedure (Table 1).7 It was reasoned that control
over the nature of the NHC structures could be achieved
through sequential alkylations of the imidazoline core.
SYNTHESIS 2014, 46, 0375–0380
Advanced online publication: 26.11.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338564; Art ID: SS-2013-M0565-OP
© Georg Thieme Verlag Stuttgart · New York

376
M. Holtz-Mulholland, S. K. Collins
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was found to participate in the alkylation and afforded the
imidazoline 3b in 60% isolated yield. Larger aromatics
could also be installed on the ligand framework. For ex-
ample, alkyl chlorides 2c and 2d, derived from 1-naphthyl
and 2-naphthyl, respectively, each participated in the al-
kylation reaction of 1. While the 1-naphthyl reagent 2c
provided a slightly lower yield of 40% for the correspond-
ing imidazoline 3c, the 2-naphthyl analogue 2d provided
the imidazoline 3d in 46% yield. Diarylmethane 2e bear-
ing two pyren-1-yl substituents performed best, yielding
monoalkylated imidazoline 3e in 68% yield.
Table 1 Alkylation of Imidazoline 1
alkylating agent
(1.1 equiv)
HN
N
N
N
R1
K2CO3 (5 equiv)
acetone
1
100 °C 2 d
Entry
Alkylating agent Product
Yielda (%)
Br
The goal of the second alkylation of the imidazolines (for
example, 3a → 4a) was to introduce a smaller substituent
that would act to modulate the reactivity of the resultant
NHC–metal complexes. As such, simple alkyl groups
such as a methyl and a benzyl were selected (Table 2). A
one-pot alkylation of 3a with iodomethane and counterion
exchange with sodium tetrafluoroborate afforded the
methyl-substituted imidazolinium salt 4a in nearly quan-
titative yield (99%) over the two steps. The synthesis of
the benzyl-substituted imidazolinium salt 4b was more
difficult, but could be accomplished via alkylation with
benzyl chloride in dichloromethane, heated at 60 °C in a
sealed tube, to afford 4b in 60% yield. Methylation of oth-
er imidazolines was also investigated. The methylation
and counterion exchange of the 1-naphthyl- and 2-naph-
thyl-substituted imidazolines afforded the corresponding
imidazolinium salts 4c and 4d in 99% yield (entries 3 and
4). The larger imidazoline 3e adorned with pyrene units
also underwent alkylation and counterion exchange, albeit
in lower isolated yield (72%) to afford 4e.
N
N
1
2
3
45
o-Tol
o-Tol
2a
3a
3b
3c
Cl
N
N
Mes
Mes
60
2b
Br
N
N
1-Nap
1-Nap
40
2c
Having demonstrated that various C1-symmetric NHC li-
gands could be generated via the dialkylation protocol, the
formation of metal complexes with the ligands was inves-
tigated. As a model, copper complexes of ligands 4a, 4b,
and 4c were prepared (Scheme 1). The methyl-substituted
complex 5a could be prepared on a gram scale using a
published procedure involving treating the salt 4a with so-
dium tert-butoxide in the presence of copper(I) chloride at
room temperature.12a The resulting complex 5a could be
isolated by column chromatography in 60% yield. The
procedure also successfully installed 4c onto copper(I)
chloride, although in diminished yield, giving 24% of 5c.
Unfortunately, the benzyl-substituted salt 4b was unstable
to the identical basic reaction conditions used for the
methyl congeners 4a and 4c. In attempting to prepare 5b,
base, temperature, or solvent were modified, but did not
afford 5b. A possible explanation for the difficulties in ob-
taining complex 5b could be competitive deprotonation of
the benzylic proton. As such, an in situ transmetalation
procedure was used employing silver(I) oxide and cop-
per(I) chloride; complex 5b could be isolated in 15–20%
yield. X-ray crystallographic analysis of 5a revealed that
the conformation of the bis(2-tolyl)methane ‘paddle’ is
effectively controlled by the tert-butyl groups on the NHC
backbone, although some influence from allylic strain be-
N
N
Cl
4
2-Nap
2-Nap
46
2d
3d
N
N
Cl
5
68
Pyr
Pyr
2e
3e
a Isolated yields after chromatography. o-Tol = 2-tolyl; Mes = mesityl;
Pyr = pyren-1-yl; 1-Nap = 1-naphthyl; 2-Nap = 2-naphthyl.
Synthesis 2014, 46, 375–380
© Georg Thieme Verlag Stuttgart · New York

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Chiral C1-Symmetric N-Heterocyclic Carbene Ligands
377
tween the bis(2-tolyl)methane ‘paddle’ and C–Cu bond Cl: 171.5°) and the complex has a buried volume similar
might be responsible for the observed orientation.11 One to the (IPr)CuCl complex (for 5a: C–Cu: 1.893 Å, %Vbur:
of the 2-tolyl groups shields one side of the copper atom. 44.5%).12b,c
The Cu–Cl bond is slightly bent (Cu–Cl: 2.107 Å, C–Cu–
Table 2 Second Alkylation To Form Imidazolinium Salts
alkylating agent
(3 equiv)
Ar
Ar
Ar
Ar
CH2Cl2
N
N
R2
N
N
X
Entry
Conditions
Product
Yielda (%)
N
N
Me
1
3a, MeI, NaBF4 (5 equiv), 21 °C, 2 d
99
BF4
4a
N
N
Bn
2
3a, BnCl, 60 °C, 15 h
60
Cl
4b
N
N
Me
3
3c, MeI, NaBF4 (10 equiv), 21 °C, 3 d
99
BF4
4c
N
N
Me
BF4
4
3d, MeI, NaBF4 (10 equiv), 21 °C, 3 d
99
4d
N
N
Me
BF4
5
3e, MeI, NaBF4 (10 equiv), 21 °C, 3 d
72
4e
a Isolated yields after chromatography.
© Georg Thieme Verlag Stuttgart · New York
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378
M. Holtz-Mulholland, S. K. Collins
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The methyl-substituted complex 5c could also be pre-
pared from the carbene formed from salt 4c and sodium
tert-butoxide. While low yields of the resulting complex
from copper(I) chloride were obtained (24%), good yields
of the complex 5c were obtained by treating the carbene
formed from 4c with copper(I) iodide (42%). X-ray crys-
tallographic analysis of 5c revealed a conformation very
similar to that of copper complex 5a (Scheme 1). The
bis(1-naphthyl)methane ‘paddle’ is again controlled by
the tert-butyl groups on the NHC backbone and shields
one side of the copper atom. The Cu–I bond is slightly
bent (Cu–I: 2.397 Å, C–Cu–I: 173.2°) and the complex
has a buried volume similar to 5a (for 5c: C–Cu: 1.894 Å,
%Vbur: 43.9%).
Following synthesis of the copper complexes 5a–c, com-
plexes 5a and 5b bearing similar counterions were evalu-
ated in oxidative couplings of 2-naphthols (Scheme 2).
These oxidative couplings represent a green and biomi-
metic chemical route towards the preparation of biaryls.13
Some of the current challenges associated with the cou-
pling of 2-naphthols involve improving asymmetric
routes and application towards the synthesis of complex
natural products.14 Utilizing metal complexes based on
metals other than copper has also been an area of intense
interest,15 and some complexes have been explored in the
challenging oxidative coupling of electronically dissimi-
lar 2-naphthols.16,17
Recently, we reported that N-heterocyclic carbene (NHC)
copper complexes6,18 could catalyze an oxidative hetero-
coupling of electron-poor and electron-rich 2-naphthols.
Preliminary investigations into the oxidative homocou-
pling of 2-naphthols began with NHC–Cu complexes 5a
and 5b using previously established conditions (Scheme
2).6 The reactivity of the catalysts 5a and 5b was purpose-
ly compared to copper-based catalyst 5d having a bulky
C2-symmetric NHC ligand in an effort to validate whether
Scheme 1 Synthesis of Cu-NHC complexes (top), X-ray crystallo-
graphic analysis of methyl-substituted complex 5a (middle: front
view, left; side view, right), X-ray crystallographic analysis of meth-
yl-substituted complex 5c (bottom: front view, left; side view, right)
CO2Me
Cu cat. (10 mol %)
AgNO3 (1.0 equiv)
CO2Me
OH
OH
OH
Oxone (1.1 equiv)
MeOH
60 °C, 15 h
6
CO2Me
7
increasing steric bulk of NHC ligand
Ph
Ph
N
N
N
N
N
N
Bn
Me
Cu
Cu
Cu
Cl
Cl
Cl
5d
5b
5a
22 %, <5% ee
22 %, <5% ee
76 %, <5% ee
with 2-picoline (1 equiv): 21% , 41% ee
with 2,6-lutidine (1 equiv): 63%, 24% ee
Scheme 2 Influence of NHC structure on the oxidative homocoupling of methyl ester 6a
Synthesis 2014, 46, 375–380
© Georg Thieme Verlag Stuttgart · New York

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Chiral C1-Symmetric N-Heterocyclic Carbene Ligands
379
13C NMR (101 MHz, CDCl3): δ = 140.7, 135.8, 130.4, 127.5, 126.4,
126.0, 70.2, 19.0.
HRMS (ESI+): m/z [M + H]+ calcd for C26H37N2: 377.2951; found:
377.2954.
the C1-symmetric NHC would allow some control over re-
activity. When methyl ester 6 was treated with copper cat-
alyst 5a, silver nitrate as a silver salt in methanol using
Oxone as the oxidant, the desired BINOL product 7 was
isolated in 76% yield. No decomposition of the catalyst or
NHC ligand was observed. Although disappointed by the
lack of enantioinduction observed, we were encouraged
by the reactivity displayed by complex 5a. Both copper
complex 5b bearing a benzyl group on the NHC ligand,
and the copper complex 5d having a bulky C2-symmetric
NHC ligand afforded only a 22% yield of BINOL 7 under
identical reaction conditions. The above results suggest
that the C1-symmetric nature of the NHC ligand having
one large and one small N-substituent was helping to af-
ford increased reactivity.
(4R,5R)-4,5-Di-tert-butyl-3-methyl-1-[bis(2-methylphe-
nyl)methyl]-4,5-dihydro-1H-imidazolium Tetrafluoroborate
(4a); Typical Procedure 2
To a solution of 3a (430 mg, 1.14 mmol) in CH2Cl2 (10 mL) was
added MeI (0.21 mL, 3.42 mmol) and NaBF4 (625 mg, 5.7 mmol).
The resulting suspension was stirred at r.t. for 2 d. The mixture was
filtered. Solvent and excess MeI were removed in vacuo giving 4a
(543 mg, >95%) as a yellow solid.
1H NMR (400 MHz, CDCl3): δ = 9.82 (s, 1 H), 8.09 (d, J = 7.8 Hz,
1 H), 7.64–7.54 (m, 2 H), 7.34 (t, J = 6.7 Hz, 2 H), 7.26–7.18 (m, 3
H), 6.13 (s, 1 H), 3.91 (d, J = 3.2 Hz, 1 H), 3.79 (s, 3 H), 3.66 (d,
J = 3.9 Hz, 1 H), 2.65 (s, 3 H), 2.15 (s, 3 H), 0.99 (s, 9 H), 0.97 (s,
9 H).
In summary, a sequential alkylation protocol was devel-
oped to rapidly generate C1-symmetric imidazolinium
salts from a readily available chiral imidazoline. The salts
can act as precursors for novel NHC ligands. Two repre-
sentative copper-based complexes were prepared and
characterized. X-ray crystallographic analysis of complex
5a and 5c highlights the effective shielding of one face of
the copper atom by an aryl group on the ligand. The cop-
per-based complexes were evaluated in oxidative cou-
pling reactions to demonstrate the increased reactivity
possible through fine-tuning of the steric properties of the
NHC ligand. Complex 5a afforded higher reactivity to-
wards oxidative coupling than both achiral and chiral cop-
per complexes bearing C2-symmetric NHC ligands.
Preliminary studies have shown that the addition of Lewis
basic additives such as 2-picoline and 2,6-lutidine influ-
ence both the yield of the oxidative coupling reaction and
the enantiomeric excess of the product 7 (Scheme 2). Ste-
ric hindrance about the nitrogen-containing heterocyclic
additive could influence the binding of the additive to the
copper center and the yield and enantioselectivity of the
process. Future work is aimed at fine tuning of the cata-
lysts and additive structure to improve the enantiomeric
excesses in the oxidative homocoupling.
13C NMR (101 MHz, CDCl3): δ = 158.8, 136.7, 134.8, 134.2, 133.8,
131.3, 130.8, 129.3, 128.9, 128.5, 128.4, 127.7, 127.1, 75.7, 73.5,
61.6, 38.8, 35.8, 35.2, 26.3, 25.4, 20.3, 19.6.
HRMS (ESI+): m/z [M]+ calcd for C27H39N2: 391.3108; found:
391.3112.
Acknowledgment
The authors acknowledge the Natural Sciences and Engineering Re-
search Council of Canada (NSERC), Université de Montréal and
the Centre for Green Chemistry and Catalysis (CGCC) for generous
funding. The Canadian Foundation for Innovation (CFI) is acknow-
ledged for generous funding of infrastructure. Francine Bélanger
and Benoît Deschênes Simard are acknowledged for X-ray crystal-
lography.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are experimental procedures and characterization data for all new
compounds. SnoIufimopg
r
tioarnStungIiooprnfit
m
rat
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Synthesis 2014, 46, 375–380
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