Asymmetric Addition of Aryl Boron Reagents to Enones with Rhodium Dicyclophane Imidazolium Carbene Catalysis

Article abstract of DOI:10.1002/anie.200352679

Chiral N-heterocyclic carbene ligands based on [2.2]paracyclophanes form complexes with rhodium. These catalysts can be used in the high-yielding and enantioselective asymmetric conjugate addition of arylboron compounds to cyclic and acyclic enones (see scheme).

Full text of DOI:10.1002/anie.200352679

Angewandte
Chemie
Rh-Catalyzed 1,4-Additions
treatment of an imidazolium salt with base and a metal,are
air-stable and can be purified by chromatography in some
cases. Alternatively,the NHC–Pd complex can be formed
in situ from the imidazolium precursor without added base.
Although numerous recent reports of NHC ligands can be
found,the area of asymmetric catalysis with chiral imidazo-
lium ligands remains in its infancy.[11]
Planar chiral [2.2]paracyclophane ligands previously have
included diphosphanes,[12] oxazoline-phosphanes,[13] oxazo-
line-imidazolium,[7c] oxazoline-selenides,[14] oxazoline-alco-
hols,[15] and Schiff base phenols. These have been used for
hydrogenation,allylic substitution,and organozinc addition
reactions.[16] Dimeric chiral [2.2]paracyclophanes are rare and
their use as catalysts has not been reported previously.[17]
The synthesis of the new ligands began with the known
compound Sp-pseudo-ortho-bromoamino[2.2]paracyclophane
(1; Scheme 1). This material can be readily accessed either
from the resolved Sp-dibromo[2.2]paracyclophane or from the
Asymmetric Addition of Aryl Boron Reagents to
Enones with Rhodium Dicyclophane Imidazolium
Carbene Catalysis**
Yudao Ma, Chun Song, Changqing Ma, Zhijun Sun,
Qiang Chai, and Merritt B. Andrus*
Rhodium–binap catalysts have been used with great success
for asymmetric conjugate additions of aryl boron compounds
to enones and other electron-deficient alkenes.[1] The
approach,pioneered by Miyaura,Hayashi,and co-workers
offers particular advantages over copper-based methods,[2]
including high selectivities,ligand availability,water toler-
ance,and moderate temperatures. Limitations remain to be
addressed,including expanding the scope to alkyl reagents,
lowering the amount of borane needed for high reactivity,and
identifying new ligands that can be modified readily to
accommodate new substrates.[3] As a first step to address
these issues and as part of an effort to identify new
asymmetric catalysts,we report herein the synthesis and use
of a novel class of chiral dicyclophane imidazolium,N-
heterocyclic carbene (NHC) ligands. Conditions are reported
for the highly selective conjugate addition of aryl borane
reagents (1.5 equiv) to cyclic and acyclic enones at moderate
temperature. These new C2-symmetric dicyclophane imida-
zolium ligands can be readily modified to allow substrate–
ligand matching with this process and in applications to other
asymmetric transformations.
Complexes of N-heterocyclic carbenes (NHC) with tran-
sition metals[4] have been developed to catalyze Heck,[5]
[4]
Suzuki–Miyaura,[6] Stille,and Kumada coupling reactions,
hydrogenation reactions,[7] and ruthenium metathesis reac-
tions.[8] We recently reported base-free conditions with
NHC–palladium catalysts for Heck and Suzuki coupling
reactions and the use of novel,bulky NHC ligands for
Sonogashira reactions.[9] Imidazolium carbene ligands pro-
vide higher stability and reactivity than phosphanes through
strong s-bond donation to the metal,together with attenuated
back-bonding through donation of the nitrogen lone pair of
electrons.[10] This combination of electronic effects renders
the metal more electron-rich,allowing a more favorable
oxidative insertion step. Typical NHC complexes,formed by
Scheme 1. Synthesis of chiral [2.2]paracyclophane imidazolium carbene
precursor ligands. R-B-PIN=B-aryl pinnacolatoborane
amino[2.2]paracyclophane.[18] The Sp-pseudo-ortho-dibro-
mide was treated with ammonia under palladium-coupling
conditions to give 1. Alternatively,Boc-protected Sp-ami-
no[2.2]paracyclophane[19] can be brominated with NBS (N-
bromosuccinimide) to give 1. Suzuki–Miyaura coupling with
aryl and cyclohexyl pinacolatoboron compounds under palla-
dium–NHC catalysis gave the amino[2.2]cyclophanes 2 in
high yields.[9a,20] A one-pot three-step procedure[21] was then
used to generate the Sp C2-symmetric dicyclophane imidazo-
lium ligands 3–6. Ligand 3 was obtained directly from the
known Sp-amino[2.2]paracyclophane.[19] Treatment with aque-
ous glyoxal gave the corresponding diimine,which was
reduced to the diamine with sodium borohydride. Triethyl
orthoformate with catalytic formic acid followed by anion
exchange with ammonium tetrafluoroborate gave the dicy-
clophane imidazolium target 3 in 61% yield. Ligands 4–6
[*] Prof. M. B. Andrus, C. Song
Department of Chemistry and Biochemistry, Brigham Young Uni-
versity
Provo, UT 84602-5700 (USA)
Fax: (+1)801-422-0153
E-mail: mbandrus@chem.byu.edu
Prof. Y. Ma, C. Ma, Z. Sun, Q. Chai
Chemistry College of Shandong University
Shanda South Road No. 27, Jinan, Shandong, 250100 (P. R. China)
[**] This work was funded by the National Institutes of Health
(GM57275, M.B.A.), Brigham Young University, and The Chemistry
College of Shandong University (Y.M.).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2003, 42, 5871 –5874
DOI: 10.1002/anie.200352679
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5871

Communications
Table 2: Variations on the conditions.
were made by following the same sequence from the Sp-
amino[2.2]cyclophanes 2 (R = phenyl,cyclohexyl,and o-
anisyl,respectively).
These new ligands 3–6 were screened in the reaction of
phenyl boronic acid (1.5 equiv) and 2-cyclohexenone under
standard conditions in THF/water (Table 1). TLC was used to
Entry
6 [mol%]
THF/H2O
T [8C]
t [h]
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
0
1
2
3
4
3
3
3
3
3
3
3
3
10:1
10:1
10:1
10:1
10:1
10:1
10:1
10:0
5:1
60
60
60
60
60
35
80
60
60
60
60
60
60
3
3
3
3
3
3
2
6
2
2
1
3
5
0
27
82
91
90
83
95
80
85
43
97
82
82
-
89
93
95
95
94
66
81
68
-
Table 1: Rh–dicyclophane imidazolium catalysis.
Entry
Ligand
t [h]
Yield [%][a]
ee [%][b]
1
2
3
4
5
3
4
5
6
6
4
8
6.5
3
3
69
86
89
96
75
61
91
97
98
95c
3:1
10:1
10:1
10:1
36a
95b
93c
[a] Reaction performed with added Na2CO3 (1 equiv). [b] Aryl boronÀic
acid: 1.2 equiv. [c] The chloride salt of ligand 6 was used instead of BF4
[a] Yield of product isolated after silica-gel chromatography. [b] Deter-
mined by chiral HPLC (OD-H column, heptane/i-propyl alcohol 98:2).
[c] Catalyst loading changed: Rh (0.2 mol%), ligand (0.3 mol%).
.
entry 8). The rate was faster when a greater proportion of
water was used,however the selectivities were much lower
(Table 2,entries 9 and 10). The use of a dioxane/water (10:1)
solvent mixture,typical conditions for Rh–binap-catalyzed
reactions,gave the product in 89% yield with 95% ee after
5 h. Methanol and methanol/water combinations gave good
reaction rates,but with lower selectivities. Added bases
investigated (Na2CO3,NaHCO ,Cs CO3,CsF,and K 2CO3);
all increased the rate of the reaction but gave poor selectivity.
When the amount of boronic acid was lowered to 1.2
equivalents,the high selectivity was maintained,but the
yield decreased (82%; Table 2,entry 12). A similar effect was
noted when the counteranion on the imidazolium salt 6 was
changed from tetrafluoroborate to chloride (Table 2,
entry 13).
The optimal reaction conditions with ligand 6 were
applied in the addition of various aryl boronic acids and
potassium trifluoroborates[1f] to several cyclic enones
(Table 3). Phenylboronic acid added to all three enones in
high yield and with good selectivity. The p-methoxyphenyl-
and o-tolylboron reagents gave similar results. The electron-
deficient reagents p-acetyl- and trifluoromethylboronic acid
also gave excellent yields and selectivities. Under these
conditions,the potassium trifluoroborate reagents reacted at
a faster rate,but with lower selectivity.
The reactions of acyclic enones with the phenylboron
reagents were also explored (Table 4). In general,the yields
were again excellent; however,the selectivities were signifi-
cantly lower. The highest selectivity in this case was found
with isopropylvinyl methyl ketone (91% ee). The trifluoro-
borate reagent again reacted at a faster rate,but with lower
selectivity.
establish when the reaction had gone to completion. The
yields shown are for isolated,purified (silica-gel chromatog-
raphy) (S)-3-phenylcyclohexanone product based on 2-cyclo-
hexenone. In the presence of [Rh(acac)(C2H4)2] (2 mol%)
and imidazolium ligand (3 mol%),high yields were obtained
at 608C for all ligands investigated. In contrast,when the
reaction was carried out with the same rhodium source but
with binap ligand,only adequate reactivity was found at
1008C.[1] Only when 0.2 mol% of the rhodium catalyst was
used did the yield of the isolated product decrease to 75% in
this case. The unsubstituted dicyclophane NHC ligand 3 gave
product with only moderate enantioselectivity (61% ee).
Ligand 4,the diphenyl variant,reacted at a slower rate,but
gave product with improved enantioselectivity (91% ee). The
dicyclohexyl ligand 5 showed further improvement (97% ee).
Dianisyl derivative 6 proved to be superior (98% ee),and the
product was isolated in an excellent yield of 96% after only
3 h.
Numerous variations of the reactions conditions were
explored for the addition of o-tolylboronic acid to cyclo-
hexanone in the presence of the rhodium–6 complex
(Table 2). With the amount of rhodium held constant at
2 mol%,the amount of imidazolium 6 was varied from 0 to
4 mol%. Without added ligand,no product was obtained
after 3 h (Table 2,entry 1). The yield was very low,27% when
1 mol% of 6 was used (Table 2,entry 2),but the selectivity
remained high at 89% ee. The optimal amount of 6 was found
to be 3 mol%,2:1 ligand/Rh,which resulted in 91% yield,
95% ee at 608C after 3 h (Table 2,entry 4). When the reaction
was stopped after 2 h,the product was obtained in 56% yield
(96% ee) (Table 2,entry 5). At 35 8C (Table 2,entry 6) a
lower yield was obtained with no improvement in selectivity.
At 808C,the selectivity dropped to 66% ee (Table 2,entry 7).
When THF alone was used without water,the reaction was
much slower and gave a lower yield and selectivity (Table 2,
3
2
The origin of the selectivity appears to be related to the
binap-catalyzed process proposed by Miyaura,Hayashi,and
co-workers.[1] These new C2-symmetric biscyclophane carbene
ligands also present four asymmetric quadrants for substrate
binding and nucleophile delivery (Scheme 2). In the absence
5872
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Chemie
Table 3: Addition to cyclic enone substrates.
Enone t, Yield [%] (ee [%])
Aryl boron
PhB(OH)2
PhBF3K
3 h,96 (98)
1 h, 96 (91)
3.5 h, 94 (93)
1 h, 93 (85)
3.5 h, 97 (92)
1 h, 95 (90)
3 h, 90 (93)
1 h, 89 (96)
3.5 h, 90 (85)
1 h, 89 (85)
3 h, 91 (95)
1 h, 95 (90)
4 h, 92 (90)
45 min, 94 (87)
Scheme 2. Origin of asymmetric induction.
4 h, 92 (95)
4 h, 89 (92)
30 min, 93 (94) 45 min, 92 (83)
allows the synthesis of numerous variations with different
electronic and steric properties. This opens up opportunities
for other rhodium-based processes and asymmetric,transi-
tion-metal-catalyzed reactions with these ligands for which
high reactivity at lower temperatures can be found. Efforts to
this end are now underway in our laboratories.
3.5 h, 96 (97)
4 h, 93 (92)
Table 4: Additions to acyclic enones.
Received: August 19,2003 [Z52679]
Keywords: addition · boron · cyclophanes ·
.
homogeneous catalysis · rhodium
Enone t, Yield [%] (ee [%])
Aryl boron
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Angew. Chem. Int. Ed. 2003, 42, 5871 –5874