Angewandte
Chemie
Table 3: Scope of the asymmetric Pd-catalyzed intramolecular a-aryla-
tion.[a]
showed that higher enantioselectivities could be achieved by
carrying out the process in polar solvents (Table 1, entries 9–
12), with tBuOH providing the best results. It is well known
that the substituent of the oxazoline moiety plays an
important role in the enantioselectivity.[12] Indeed, the use of
a more sterically encumbered tBu-phox (L9a) increased the
optical purity of the product to 81% ee (Table 1, entry 14).
Particularly significant is the effect of the a-substituent to the
aldehyde (see below), thus, 1b afforded the desired com-
pound 2b in 85% yield and 86% ee (Table 1, entry 15).
We next focused on the influence of both steric and
electronic effects of the phosphine moiety of the phox ligands
(Table 2). Although we observed no clear trend in electronic
Entry
R
n
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
Me (1a)
iPr (1b)
Et (1c)
tBu (1d)
Cy (1e)
1
1
1
1
1
1
1
1
2
2
64
86
58
88
87
81
73
87 (S)
94 (R)
88 (S)
96 (R)
96 (R)
98 (R)
98 (S)
98 (R)
53 (R)
63 (R)
Ph (1 f)
2-(MeO)C6H4 (1g)
2-MeC6H4 (1h)
iPr (1i)
[a]
27 (36)[d,e]
69
53
Table 2: Screeningof different phox ligands.
10
Ph (1j)
[a] Aldehyde (0.5 mmol) in tBuOH (5 mL), Cs2CO3 (0.65 mmol),
Pd(OAc)2 (3 mol%), L (9 mol%), 808C, 24 h. [b] Yields of isolated
products are an average of at least two independent runs. [c] The ee
values were determined by chiral GC or HPLC. [d] Values in parentheses
correspond to the yield of isolated product obtained using5 mol% of
Pd(OAc)2 and 15 mol% of L9i. [e] Incomplete conversion of substrate
was observed.
Entry
R
L
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
cyclopentyl
2-MeC6H4
3,5-(CF3)C6H4
2-furyl
cyclohexyl
4-MeC6H4
4-(CF3)C6H4
4-(MeO)C6H4
4-(MeO)C6H4
L9b
L9c
L9d
L9e[d]
L9 f
L9g
L9h
L9i
66
32
47
69
85 (R)
55 (R)
78 (R)
83 (R)
80 (R)
90 (R)
90 (R)
94 (R)
94 (R)
69[e]
88[e]
77[e]
79[e]
93[e,f]
of the alkyl substituent, enantioselectivity increased with the
size of the a-substituent to the carbonyl group (Table 3,
entries 1–5). Under our reaction conditions, o-tolyl derivative
1h proved to be a difficult case, in which even higher catalyst
loadings produced the desired product 2h in only 36% yield,
but with 98% ee (Table 3, entry 8).[14] The efficiency of the
method dropped significantly for substrates forming a six-
membered ring; tetrahydronaphthalene derivatives were
prepared in moderate to good yields with moderate enantio-
selectivities (Table 3, entries 9–10). The absolute configura-
tion of two of the products was established by X-ray
crystallography of 2g (Figure 1)[15] and by comparison with
a reported compound derived from 2a.[16,17]
L9i
[a] Aldehyde (0.1 mmol) in tBuOH (1 mL), Cs2CO3 (0.12 mmol),
Pd(OAc)2 (3 mol%), L (9 mol%), 808C, 15 h. [b] GC yields using
dodecane as internal standard. [c] The ee values were determined by
chiral GC analysis. [d] DABCO (13.5 mol%) was used [13]. [e] Cs2CO3
(1.3 equiv) was used. [f] The reaction was carried out for 24 h at 808C.
effects of the phosphine in the enantioselectivity and the yield
of the reaction (Table 2, entry 7 vs 8), the size of the
substituents has a substantial impact. Along these lines, the
use of bulkier phosphine substituents resulted in lower
enantioselectivity (Table 2, entry 2 vs 6). As depicted in
Table 2, the best results were obtained when the reagents
were stirred at 808C for 24 h using Cs2CO3 as the base and
ligand L9i in tBuOH (0.1m) affording the desired indane
derivative 2b in 94% ee and 93% yield, respectively (Table 1,
entry 9).
Figure 1. Molecular structure of 2g with ellipsoids set at 50% proba-
bility. Hydrogen atoms are omitted for clarity.
With the optimized reaction conditions in hand, we
further investigated the influence of the a-substituent to the
aldehyde on the reaction outcome (Table 3). Substrates
containing both a-alkyl and a-aryl substituents yielded the
product aldehydes in high enantioselectivity. Generally,
substrates with a-aryl substituents gave rise to products with
higher optical purity than these with a-alkyl analogues
(Table 3, entries 1–5 vs entries 6–8). In regard to the nature
The fact that products with both aryl as well as alkyl a-
substituents were of the same absolute configuration suggests
that the enantioselectivity-limiting step in the catalytic system
is common for both classes of substrates.
The influence of the substitution pattern in the aromatic
ring on the outcome of the reaction is shown in Table 4. The
Angew. Chem. Int. Ed. 2008, 47, 8108 –8111
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