Communications
formed by
a
recently developed, efficient oxidative
the product with 75% ee (Table 1, entry 1). Electron-with-
drawing substituents on the terminal benzene ring were
detrimental to the yield and the selectivity (Table 1, entries 2,
3). The pronounced influence of ortho-substituents is indi-
cated by the change of the stereochemical outcome of the
reaction (Table 1, compare entries 1 and 2). An electron-
donating para-methoxy group on the other hand increased the
level of selectivity (Table 1, entry 4). Two alkoxy groups on
the terminal benzene ring gave even better ee values (Table 1,
entries 5–8), with the 3,4-dimethoxy motif derived from
veratraldehyde being optimal for stereocontrol. Oxazolines
derived from phenylalaninol, valinol, and aminoindanol
performed almost equally well (Table 1, entries 5, 13, 16),
but tert-leucinol- or phenylglycinol-derived ligands showed
significantly lower ee values (Table 1, entries 14, 15).
method.[15] Deprotonation and coupling of the methyl group
to the corresponding phosphonate was followed by a Horner–
Wadsworth–Emmons reaction with 3,4-dimethoxybenzalde-
hyde, providing olefin–oxazoline 5 in 26% overall yield.
Alternative synthetic routes starting from 2-bromomethyl-
benzonitrile were also developed (Scheme 3).[16]
Using 1 mol% active catalyst derived from the most
selective ligand, phenylalaninol derived 5, product 24Aa was
obtained in 93% ee and, using only 0.1 mol% of catalyst,
90% ee was still obtained (Table 1, entries 5, 6). Ligand 16,
containing a sterically more demanding oxazoline derived
from (À)-menthone[17] does not give any product (Table 1,
entry 17). Ligands with a doubly ortho-substituted terminal
benzene ring (8,9), with a triphenylethylene backbone (17),
or the potentially tridentate ligand 18 did also not provide
catalytically active complexes (Table 1, entries 9, 10, 18, 19).
The latter observation is in accordance with the generally
accepted mechanism of the rhodium-catalyzed conjugate
addition,[14] in which two of the four available coordination
sites of the metal are needed for complexation of the enone
and the aryl nucleophile. This large series of olefin–oxazolines
with its marked reactivity and selectivity differences demon-
strates the modularity, tunability, and adaptability of this new
ligand class.
Scheme 3. Modular ligand assembly, retrosynthetic analysis.[16]
As a test reaction for this new family of ligands, we chose
the rhodium-catalyzed conjugate addition of phenylboronic
acid to cyclohexenone (Table 1).[14]
With the unsubstituted parent system, ligand 1, the
reaction proceeded smoothly and yielded more than 90% of
Table 1: Screening of ligands 1–18 in the conjugate addition of phenyl-
boronic acid to cyclohexenone.[a]
With ligand 5 identified as the most suitable ligand, we
screened the substrate scope for this particular ligand in the
conjugate addition reaction. A series of representative enones
and boronic acids were allowed to react under the standard
conditions (Table 2). These reactions demonstrated the broad
applicability of ligand 5 to different substrates. Different ring
sizes as well as ortho-, meta-, and para-substituents on the
arylboronic acid are well tolerated (Table 2, entries 1–10).
Even a quaternary center is built up with good ee value,
although far less effectively in terms of yield (Table 2,
entry 11).[18]
Entry
Ligand
Yield[b] [%]
ee[c] [%]
1[d,e]
2[d,e]
3
1
2
3
4
5
5
6
7
91
60
50
78
88
88
92
97
0
75 (S)
51 (R)
69 (S)
81 (S)
93 (S)
90 (S)
80 (S)
85 (S)
–
4
5
6[f]
7[g]
8
9
8
9
10
11
12
13
14
15
16
17
18
19
0
–
Especially interesting is the unprecedented coordination
mode of this new ligand class. The 1H NMR spectrum of a Rh
complex of ligand 5 and [Rh(C2H4)2Cl] revealed a strong
coordination between olefin and rhodium, as shown by the
upfield shifts of the olefinic protons from d = 8.85 ppm and
7.11 ppm (J = 16 Hz) in the free ligand to d = 5.49 and
4.49 ppm (J = 12 Hz) in the complex. Furthermore, the
olefin–rhodium interaction was unequivocally demonstrated
by single-crystal X-ray analysis of crystals obtained by slow
diffusion of pentane into a dioxane solution of a complex
derived from ligand 12 and [Rh(C2H4)2(acac)] (Figure 1;
acac = acetylacetone).[19] In this complex, ligand 12 and acac
were both found to act as bidentate, chelating ligands to give a
10
11
12
13
14
15
16
17
18
83
86
97
74
91
93
0
50 (S)
86 (S)
89 (S)
30 (S)
64 (R)
85 (R)
–
0
0
–
–
[a] General procedure: 0.005 mmol [{Rh(C2H4)2Cl}2] and 0.011 mmol
ligand were stirred at 408C with 1.5 mmol PhB(OH)2, 1 mmol cyclo-
hexenone, and 0.3 mmol KOH in dioxane/H2O 10:1 until GC-MS showed
the absence of starting material. [b] Yield of isolated product. [c] Deter-
mined by HPLC on chiral stationary phases. [d] 5 mol% [{Rh(C2H4)2Cl}2]
and 11 mol% ligand were used. [e] Reaction run on 0.3 mmol scale.
[f] Reaction run with 0.1 mol% catalyst at 608C. [g] Reaction run at 608C.
pseudo-square-planar coordinated RhI center. The Rh C
À
bond lengths (2.088 ꢀ and 2.097 ꢀ) are typical for olefin
1144
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 1143 –1146