.
Angewandte
Communications
catalysis,[11] that is, serve 1) as a Lewis base to bind a metal,
2) as a hydrogen-bond acceptor to activate a substrate, and
3) to provide more of a chiral environment. Herein, we report
a new class of chiral bis(sulfoxide) phosphine(BiSO-P)
ligands, and employ them in an unprecedented palladium-
Table 1: Palladium-catalyzed asymmetric allylic alkylation of 5a with
unsymmetric allyl acetates.[a]
Entry
L
1
Base
6a/7a[b]
Yield
[%][c]
ee
[%][d]
catalyzed DYKAT of racemic unsymmetrical 1,3-disubsti-
tuted allylic acetates with indoles [Eq. (3)].
1
2
3
4
5
6
7
8
L1
L2
L3
L4
(R)-binap
Trost-L
Trost-L
Trost-L
L3
L3
L3
L3
L3
1a
1a
1a
1a
1a
1a
1b
1c
1b
1c
1a
1a
1a
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
Cs2CO3
97:3
20
76
72
72
12
trace
70
63
70
43
80
90
60
95:5
95:5
90:10
85:15
n.d.
86:14
95:5
85:15
85:15
98:2
94:6
96:4
27
n.d.[e]
rac
rac
44
9
10
11
12
13f
72
29
65
89
88
94
82
90(84)[g]
Scheme 1. Synthesis of BiSO-P ligands.
[a] Reaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), base (0.4 mmol),
[{PdCl(C3H5)}2] (0.005 mmol; 2.5 mol%), ligand (0.012 mmol; 6 mol%)
and THF (2 mL). Reactions were conducted under argon at 408C for
48 h. [b] Analysis of the crude reaction mixture by 1H NMR spectroscopy.
[c] Combined yields of 6a and 7a based on 1. [d] The ee value of 6a was
determined by HPLC analysis using a chiral stationary column. [e] Not
detected. [f] 158C, 4 equiv of Cs2CO3 was used as base. [g] Yield of
isolated 6a. Boc=tert-butoxycarbonyl, THF=tetrahydrofuran.
The ligands L2–L4 were synthesized as shown in
Scheme 1. Under an inert gas atmosphere and at À788C,
two equivalents of phenyl tert-butyl sulfoxide was deproton-
ated by n-butyllithium and then reacted with one equivalent
of the substituted (pyrrolyl, piperidinyl, and N-diethyl)
phosphine dichloride. After workup, the bis(sulfoxide) phos-
phines (BiSO-P) were obtained as white solids in 24–35%
yields.
With the novel BiSO-P ligands in hand, we initially
attempted the asymmetric indolylation of 1a in the presence
of [{PdCl(C3H5)}2] and K2CO3 at 408C. The previous sulfoxide
phosphine L1 resulted in a low yield and ee value (Table 1,
entry 1). The new ligands L2–L4 improved both the reactivity
and enantioselectivity significantly (Table 1, entries 2–4) and
provided (S)-6a, whose absolute configuration was deter-
mined by analysis of the single-crystal X-ray structure.[12] In
contrast, (R)-binap was also tested in this model reaction and
led to 27% ee of the product with a rather low reactivity
(Table 1, entry 5). Trost-L catalyzed the reaction of allylic
carbonates 1b and 1c with indole to give nearly racemic
products (Table 1, entries 6–8). In the presence of the best
ligand, L3, the base Cs2CO3 was found to efficiently improve
reactivity, albeit with a small reduction in enantioselectivity
(Table 1, entry 12). Fortunately, an excellent ee value (94%)
and yield (94%; 84% for isolated product) of 6a were
obtained at 158C with four equivalents of Cs2CO3 as the base
(Table 1, entry 13; (for detailed screening of reaction con-
ditions, see the Supporting Information). From these results, it
appears that the reaction can be realized through a deracem-
ization (DYKAT or dynamic kinetic resolution) pathway
promoted by the BiSO-P ligands.
acetates could react with 1H-indole to get highly regioselec-
tive 3-allylindoles with excellent yields. Electron-rich sub-
stituents on the phenyl ring, such as para-, meta-, and ortho-
methoxy groups, as well as meta- and para-methyl groups gave
higher enantioselectivities. The major products 6a–6e were
afforded with excellent ee values (87–95%) and high yields
(76–84%) of the isolated products. Substrates with electron-
deficient phenyl rings (para-chloro, para-bromo, and meta-
fluoro) also proceeded well and provided the major products
with good enantioselectivities (84–87%) and yields (70–
78%). In addition, the heteroaromatic substrate thiophenyl
was quite reactive and provided 6j. Particularly, some of 1,3-
dialkyl allylic acetates were also suitable substrates for this
transformation. For instance, when R was nPr (1m), iPr (1n),
and cyclohexyl (1o), the corresponding 3-allylindoles 6k, 6l,
and 6m were obtained with good to excellent regioselectiv-
ities, as well as high enantioselectivities (Table 2, entries 11–
13).[13]
We next investigated the scope of indole nucleophiles
(Table 2, entries 14–24). Various 4-, 5-, 6-, or 7-substituted
indoles (5b–5l) smoothly reacted with 4-(4-methoxyphenyl)
but-3-en-2-yl acetate (1a) to deliver highly optically active 3-
allylical indole derivatives (84–95% ee), with good yields (63–
83%) of the isolated products. The electronic properties of
the indole nucleophiles show no significant impact on the
The substrate scope of this palladium-catalyzed allylation
is summarized in Table 2. Various 4-substituted but-3-en-2-yl
2
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Angew. Chem. Int. Ed. 2013, 52, 1 – 6
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