A chiral 6-membered n -heterocyclic carbene copper(I) complex that induces high stereoselectivity

Article abstract of DOI:10.1021/ol1021756

A chiral 6-membered annulated N-heterocyclic (6-NHC) copper complex that catalyzes β-borylations with high yield and enantioselectivity was developed. The chiral 6-NHC copper complex is easy to prepare on the gram scale and is very active, showing 10000 turnovers at 0.01 mol % of catalyst without significant decrease of enantioselectivity and with useful reaction rates.

Full text of DOI:10.1021/ol1021756

ORGANIC
LETTERS
2010
Vol. 12, No. 21
5008-5011
A Chiral 6-Membered N-Heterocyclic
Carbene Copper(I) Complex That
Induces High Stereoselectivity
Jin Kyoon Park, Hershel H. Lackey, Matthew D. Rexford, Kirill Kovnir,
Michael Shatruk, and D. Tyler McQuade*
Department of Chemistry & Biochemistry, Florida State UniVersity, Tallahassee,
Florida 32306-4390, United States
mcquade@chem.fsu.edu
Received September 10, 2010
ABSTRACT
A chiral 6-membered annulated N-heterocyclic (6-NHC) copper complex that catalyzes ꢀ-borylations with high yield and enantioselectivity was
developed. The chiral 6-NHC copper complex is easy to prepare on the gram scale and is very active, showing 10 000 turnovers at 0.01 mol
% of catalyst without significant decrease of enantioselectivity and with useful reaction rates.
N-Heterocyclic carbenes (NHCs) are excellent organocata-
lysts and ligands.1 6-Membered N-heterocyclic carbene
(6-NHC) metal complexes have unique electronic and
steric properties2 and show improved properties over
5-NHCs in some cases.2b,c,i In surprising contrast to
organocatalytic carbenes,3 however, no fused cyclic NHC-
metal catalysts with rigid chiral groups have exhibited high
enantioselectivity.4 Recognizing the strengths of both 6-N-
HCs and annulated NHCs, we designed a 6-NHC with a rigid
core (imidazoquinazoline) formed by segments B and C,
steric blockade D, and chiral group A (Figure 1). Here, we
present the synthesis of this new ligand and its rhodium and
copper(I) complex. We also demonstrate that copper(I)
complex can induce high enantioselectivity in a known
reaction.
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For phenanthroline core, see: (c) Metallinos, C.; Du, X. Organometallics
2009, 28, 1233. For biisoquinoline core, see: (d) Seo, H.; Hirsch-Weil, D.;
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10.1021/ol1021756  2010 American Chemical Society
Published on Web 10/04/2010

Figure 1. Design of the 6-NHC ligand.
Ligand precursor 1 was prepared as shown in Scheme 1.
Fluoroimidazoline was synthesized via a known method5a
Scheme 1. Synthesis of the 6-NHC Precursor 1
Figure 2
(bottom).
.
1H NMR data of a mixture of 2 and 3 (top) and only 3
and the mesityl group was installed by using a nucleophilic
aromatic substitution in 99% yield.5b Subsequent annulation
with NH4BF4/triethyl orthoformate provided the carbene
ligand precursor in 95% yield.
Salt 1 is a shelf-stable compound that is readily converted
into metal complexes by two standard approaches. The first
approach is to generate a carbene via addition of a suitable
base such as lithium hexamethyldisilazide followed by
addition of an appropriate metal salt.2e,f,j We used this
method to synthesize a 1-Rh complex that manifests itself
as a mixture that includes a 1:1 rhodium:1 and a 2:1
rhodium:1 species. The 1H NMR spectrum shown in Figure
2 exhibits two sets of peaks that we have assigned as the
mono- and dirhodium species. The monorhodium species can
be produced by treating the mixture with supported or free
pyridine.
The stucture established by X-ray single-crystal diffraction
confirms our assignment of the NMR data as both the
dirhodium [(COD)Rh(µ2-1)Rh(COD)] species (2) species
and monorhodium [(COD)Rh(1)] species (3) (COD ) 1,5-
cyclooctadiene) are cocrystallized in the unit cell of the
complex (Figure 3). The structures also enable an analysis
of the ligand geometry. It is evident from the data that the
annulated ligand 1 is planar and that the central ring is
aromatic as indicated by the near 120° bond angles and
symmetric bond lengths. The crystal structure also demon-
trates that the mesityl group provides a steric blockade on
one side of the ligand and the diaminodiphenylethylene
moiety provides a chiral pocket.
Figure 3. Dirhodium (2) and monorhodium (3) species cocrystal-
lized in the structure of the 1-Rh complex.
far, the resulting compound is an orange, shelf-stable solid
that exhibits NMR and elemental analysis consistent with
complex 4 (Scheme 2). This copper(I) species was explored
Scheme 2. Synthesis of the 6-NHC Copper Chloride 4
The second method used to make metal-1 complexes
combines 1 with a metal salt followed by addition of a base.
The title copper(I) complex was made in this way5c and
though a crystal structure of this species has alluded us thus
Org. Lett., Vol. 12, No. 21, 2010
5009

for catalytic activity and, as we discuss below, the catalyst
shows excellent properties, suggesting that our 6-NHC ligand
provides the necessary electronic and steric characteristics.
The conjugate addition of boron to electron-poor alkenes
(ꢀ-borylation) provides access to intermediates useful in the
construction of complex products. Prior studies reveal that
copper(I) catalysts yield ꢀ-borylations with greater selectivity
than other transition metals,6,7 presumably via a Cu-B
species.8,9 Though both chiral phosphine and 5-NHCs are
competent ligands for copper(I)-catalyzed ꢀ-borylations,
phosphine catalysts generally have exhibited higher enanti-
oselectivity.7 Hoveyda’s group, however, used a 5-NHC-
copper complex to hydroborate trisubstituted electron-poor
alkenes and styrenic alkenes with high yield and
selectivity,7a,10a and also demonstrated an organocatalytic
method requiring only a NHC to catalyze ꢀ-borylations.10b
Thus far, no 6-NHC-copper complexes induce high enanti-
oselectivity for ꢀ-borylation reactions. On the basis of the
reported success of copper(I)-catalyzed ꢀ-borylations, we
chose this reaction as a model for determining if our 6-NHC
ligand could induce high enantioselection.
Table 1. Substrate Scope for ꢀ-Borylated Ester Synthesisa
Exploratory studies11 revealed that 4 is a highly active
catalyst for ꢀ-borylations, providing complete consumption
of starting materials within 1 min (1 mol % catalyst; 0 °C)
in diethyl ether to give 78% ee of the desired product.
Optimization revealed that higher selectivity could be realized
at -55 °C and that methanol was a necessary additiVe.
Complex 4 was successful at transforming a variety of
aliphatic and aromatic R,ꢀ-unsaturated esters to ꢀ-borylated
products in high yield and enantioselectivity (Table 1). Linear
aliphatic substrates such as ethyl hexenoate and ethyl
octenoate had high enantioselectivities of 90% and 91%,
respectively (entries 2 and 3). Increased γ-branching was
also well tolerated (entries 4-6). Methyl cinnamate gave the
highest ee (87% ee) among the methyl, ethyl, and isobutyl
a Reactions run under N2 atm and repeated more than 2 times. b Isolated
yields. c Determined by GC or HPLC after oxidizing the boronate to alcohol
by the treatment with H2O2/NaOH. d Toluene as solvent. e 3 mol % catalyst
was used. f Reactions run at -30 °C.
esters of cinnamic acid, which is opposite to the crotonate
esters (90% ee) (entries 1 and 7).11 Ortho-substituted
cinnamate esters also showed high selectivity (entries 9 and
10). These data indicate that the 6-NHC ligand induces high
enantioselectivity.
(5) (a) Busacca, C. A.; Lorenz, J. C.; Grinberg, N.; Haddad, N.; Lee,
H.; Li, Z.; Liang, M.; Reeves, D.; Saha, A.; Varsolona., R.; Senanayake,
C. H. Org. Lett. 2008, 10, 341. (b) Davis, E. M.; Nanninga, T. N.; Tjiong,
H. I.; Winkle, D. D. Org. Process Res. DeV. 2005, 9, 843. (c) Jurkauskas,
To quantify the activity of 4, we reduced the catalyst
loading (Table 2). At 0.01 mol % of 4, the reaction proceeded
V.; Sadighi, J. P.; Buchwald, S. L. Org. Lett. 2003, 5, 2417
.
(6) (a) Ito, H.; Yamanaka, H.; Tateiwa, J.; Hosomi, A. Tetrahedron Lett.
2000, 41, 6821. (b) Takahashi, K.; Ishiyama, T.; Miyaura, N. J. Organomet.
Chem. 2001, 625, 47. (c) Mun, S.; Lee, J.-E.; Yun, J. Org. Lett. 2006, 8,
Table 2. Catalyst Loading Experiment
4887. (d) Lee, J.-E.; Kwon, J.; Yun, J. Chem. Commun. 2008, 733
.
(7) (a) O’Brien, J. M.; Lee, K.-s.; Hoveyda, A. H. J. Am. Chem. Soc.
2010, 132, 10630. (b) Schiffner, J. A.; Mu¨ther, K.; Oestreich, M. Angew.
Chem., Int. Ed. 2010, 49, 1194. (c) Feng, X.; Yun, J. Chem. Commun. 2009,
6577. (d) Chen, I.-H.; Yin, L.; Itano, W.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2009, 131, 11664. (e) Sim, H.-S.; Feng, X.; Yun, J. Chem.sEur.
J. 2009, 15, 1939. (f) Lillo, V.; Prieto, A.; Bonet, A.; Dia´z-Requejo, M. M.;
Ramie´z, J.; Per´ez, P. J.; Ferna´ndez, E. Organometallics 2009, 28, 659. (g)
Fleming, W. J.; Mu¨ller-Bunz, H.; Lillo, V.; Ferna´ndez, E.; Guiry, P. J. Org.
Biomol. Chem. 2009, 7, 2520. (h) Lee, J.-E.; Yun, J. Angew. Chem., Int.
entry ester mol % time (min) convn (%)d ee (%) TON
1a
2a
3b
4b
5c
44 mg 10
44 mg
0.44 g 0.1
0.44 g 0.05
<1
<1
3
80
100
>99
>99
>99
92
91
88
87
88
10
100
1 000
2 000
10 000
1
Ed. 2008, 47, 145
.
(8) (a) Laitar, D. S.; Tsui, E. Y.; Sadighi, J. P. J. Am. Chem. Soc. 2006,
128, 11036. (b) Laitar, D. S.; Mu¨ller, P.; Sadighi, J. P. J. Am. Chem. Soc.
>99
2.0 g
0.01
>99 (93)e
2005, 127, 17196
.
(9) (a) Zhao, H.; Dang, L.; Marder, T. B.; Lin, Z. J. Am. Chem. Soc.
2008, 130, 5586. (b) Dang, L.; Lin, Z.; Marder, T. B. Chem. Commun.
2009, 3987. (c) Lillo, V.; Bonet, A.; Ferna´ndez, E. Dalton Trans. 2009,
a 0.2 M. b 0.4 M. c 0.8 M. d Determined by GC. e Isolated yield.
2899. (d) Dang, L.; Lin, Z.; Marder, T. B. Organometallics 2008, 27, 4443
(10) (a) Lee, Y.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 3160.
(b) Lee, K.-s.; Zhugralin, A. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2009,
.
within 100 min with high yield and enantioselectivity (entry
5). Though NHC-copper catalysts are known to provide very
high turnover numbers (TONs),12 we are unfamiliar with an
asymmetric case with this activity.
131, 7253
(11) See the Supporting Information.
.
(12) Diez-Gonzalez, S.; Nolan, S. P. Angew. Chem., Int. Ed. 2008, 47,
8881.
5010
Org. Lett., Vol. 12, No. 21, 2010

In summary, we have synthesized a new annulated, chiral
carbene precursor (1) and produced two new metal com-
plexes using this ligand. The 6-NHC-rhodium complexes
yield a crystal structure that reveals the 6-NHC to be planar
about the carbene and the central ring to be aromatic. The
6-NHC-copper(I) complex (4) catalyzes ꢀ-borylations with
high yield and enantioselectivity illustrating that the 6-NHC
ligand provides an excellent chiral environment. The catalyst
is also very active, showing 10 000 turnovers at 0.01 mol %
of catalyst without significant decrease of enantioselectivity
and with useful reaction rates indicating that the 6-NHC
ligand provides an electronic environment about copper that
enables high reactivity. Further studies concerning the
mechanism and expansion of reaction scope are underway.
Acknowledgment. The authors thank NSF (CHE-0809261),
and FSU support and FSU VP of Research and Dean of A&S
for NMR upgrades. J.K.P. thanks the OLED group, LG
Chem, Ltd.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data of the reaction products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL1021756
Org. Lett., Vol. 12, No. 21, 2010
5011