Angewandte
Chemie
ee (Table 1, entry 8).The question that still remained open at
this stage and needed answering was that of the role of the o-
aryl substituent.
The imidazolium salts 7d and 7e (Scheme 3) were to shed
light on this question and the requisite amines were synthe-
sized by arylnitrile alkylation with tBuMgCl in the presence of
CuBr as catalyst, followed by in situ reduction with NaBH4.
This procedure afforded the primary amines rac-8a and rac-
8b in 80% and 82% yield, respectively (Scheme 3).
Scheme 2. Synthesis of imidazolium salts (R,R)-7a–c. Identical proce-
dures were used for (S,S)-7a–c. OTf=triflate.
by anion metathesis with NaI to give 7b and 7c.This also
removed residual silver salts (Scheme 2, lower route).
Hartwig and Leeꢀs conditions were applied in our study to
compare results with those depicted in Scheme 1; the results
are shown in Table 1.The ligand 7a with methyl groups at the
stereogenic benzylic centers afforded the oxindole in accept-
able yield but very low enantiomeric excess (ee value; Table 1,
entry 1).
The result was markedly improved with ligand 7b
(Table 1, entry 2) which shows much higher induction and
also a switch in asymmetric induction.A further significant
increase in product ee value occurred when ligand 7c was
used (Table 1, entry 3).Changing the solvent to dioxane
produced very similar results in both yield and asymmetric
induction (Table 1, entry 4).In aromatic solvents, the reaction
is sluggish but can be driven to completion by heating.The
ee values in these reactions were however considerably lower
Scheme 3. Synthesis of the amines rac-8a and rac-8b followed by
resolution and conversion into the imidazolium salts 7d and 7e (R,R)-
enantiomers shown).
An enantiopure sample of (R)-8a was obtained according
to a literature procedure,[17] and enantiomerically pure
imidazolium salt (R,R)-7d was obtained using the same
procedure as described for (R,R)-7c. Rac-8b was resolved by
forming the diastereoisomeric salt with l-malic acid in
ethanol.Other acids tested included N-acetyl leucine, man-
delic acid, tartaric acid, camphor sulfonic acid, and 5-oxopro-
line, but their performance as resolving agent of 8b was very
poor.The ( S,S)-salt of malic acid/8b crystallized preferen-
tially (97:3 d.r.) and a second recrystallization afforded, after
separation, the amine (S)-8b in 33% overall yield (max. =
50%) and > 99% ee.The imidazolium salt ( S,S)-7e was
synthesized as detailed for (R,R)-
(Table 1, entries 5 and 6).CH Cl2 was not a suitable solvent;
2
no oxindole product was formed and decomposition was
evident.Going back to DME and switching from [Pd(dba) ]
2
(dba = trans,trans-dibenzylideneacetone) to Pd(OAc)2 pro-
duced a near-identical result in the two reactions (Table 1,
entries 3 and 7).The reaction time could be shortened to 14 h
by heating to 508C but with a small erosion of both yield and
7c. (R,R)-7e was prepared analo-
Table 1: Chiral carbene ligands in the palladium-catalyzed intramolecular cyclization of amide 1 to
oxindole 2.[a]
gously from (R)-(+)-8b and its
absolute configuration was deter-
mined by X-ray analysis (see
EntryL*
[Pd]
T [8C] t [h] Solvent
Yield of 2 ee [%][c] Optical
Config[d]
[%][b]
rotation
Supporting
Information).[18]
Applying (R,R)-7d to the asym-
metric cyclization afforded product
2 efficiently, albeit in modest en-
1
2
3
4
5
6
7
8
9
10
(R,R)-7a [Pd(dba)2] 23
(S,S)-7b [Pd(dba)2] 23
(S,S)-7c [Pd(dba)2] 23
(S,S)-7c [Pd(dba)2] 23
(S,S)-7c [Pd(dba)2] 23
(S,S)-7c [Pd(dba)2] 75
24
24
24
24
24
24
24
14
24
24
DME
DME
DME
dioxane
toluene
72
93
96
94
20
16
77
87
85
73
67
87
84
57
94
(À)
(À)
(À)
(À)
(À)
(À)
(À)
(À)
(+)
(À)
S
S
S
S
S
S
S
S
R
S
antiomeric
purity
(Table 1,
entry 9).With the importance of
the ortho-aryl substituent estab-
lished, the question of ether
versus alkyl group was probed.
The result in Table 1, entry 10
shows that the chiral carbene
ligand derived from 7e tops the
performance of that based on 7c.
These two chiral carbene ligands
benzene 96
(S,S)-7c Pd(OAc)2
(S,S)-7c Pd(OAc)2
23
50
DME
DME
DME
DME
98
90
(R,R)-7d [Pd(dba)2] 23
(S,S)-7e [Pd(dba)2] 23
98
99[e]
[a] Conditions: 0.25 mmol 1, 0.05m in the indicated solvent, [Pd] 5 mol%, L* 5 mol%, 1.5 equiv
NaOtBu. dba=trans,trans-dibenzylideneacetone. [b] Yield of isolated product after flash chromatog-
raphy. [c] Determined by HPLC chromatography (Chiralcel ODH). [d] Assigned on the basis of the X-ray
structure determination of (À)-(S)-10. [e] 1-mmol scale.
Angew. Chem. Int. Ed. 2007, 46, 8484 –8487
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8485