Catalytic enantioselective allylation of ketimines by using palladium pincer complexes with chiral bis(imidazoline)s

Article abstract of DOI:10.1002/chem.201300685

Get selective! Enantioselective allylation of ketimines derived from isatins by using chiral 1,3-bis(imidazolin-2-yl)benzene (Phebim)-Pd^II complexes afforded products with good enantioselectivity (see scheme). The reaction was applied to a wide variety of ketimines. The obtained product can be converted to homoallylic amines and a spirocyclic amine without the loss of enantiopurity. Copyright

Full text of DOI:10.1002/chem.201300685

DOI: 10.1002/chem.201300685
Catalytic Enantioselective Allylation of Ketimines by Using Palladium Pincer
Complexes with Chiral Bis(imidazoline)s
Shuichi Nakamura,* Kengo Hyodo, Masayuki Nakamura, Daisuke Nakane, and
Hideki Masuda[a]
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Chem. Eur. J. 2013, 19, 7304 – 7309

COMMUNICATION
The development of mild, catalytic, and enantioselective
enantioselective allylation of such compounds has not been
reported.[8,9] Recently, we reported the enantioselective de-
carboxylative addition of malonic acid half-thioesters
(MAHTs) to ketimines derived from isatins by using bifunc-
tional organocatalysts.[10] On the other hand, we also devel-
oped palladium pincer complexes with 1,3-bis(imidazolin-2-
yl)benzene (Phebim).[11–13 ] Herein, our interest was extend-
ed to the enantioselective allylation of ketimines derived
from isatins by using bis(imidazoline)–palladium pincer
complexes (Figure 2).[14] To our knowledge, this is the first
example of enantioselective allylation of ketimines derived
from isatins.
À
versions of C C bond-forming processes is a topic of para-
mount importance in modern organic chemistry. In this con-
text, the enantioselective allylation of ketimines by using
chiral catalysts attracts a great deal of interest, as it provides
efficient access to chiral homoallylic amines containing a
quaternary carbon center. In particular, the utilization of ke-
timines derived from isatins has attracted much attention,
because the reaction affords chiral 3-substituted 3-amino-2-
oxindole derivatives, which are an important structural
motif in biologically active compounds,[1] such as AG-
041R,[2] chartelline C,[3] and NITD609[4] (Figure 1). Especial-
ly, the allylation of ketimines derived from isatins affords
homoallylic aminooxindole derivatives, which act as an in-
hibitor of HIV-1 protease.[5] Furthermore, spirocyclic amino-
oxindole frameworks are present in a large number of bioac-
tive, naturally occurring alkaloids and medicinally relevant
compounds.[6]
Figure 2. Enantioselective allylation of ketimines derived from isatins by
using chiral palladium complexes.
We first examined the reaction of ketimine 1a derived
from N-benzylisatin with allyltrimethoxysilane as an allylat-
ing reagent in the presence of 5 mol% of various chiral cat-
alysts 3a–h and silver fluoride (1.0 equiv) in THF. The re-
sults are shown in Table 1.
Table 1. Enantioselective allylation of ketimines 1a–d derived from N-
benzylisatins using 3a–h.
Figure 1. Biologically active 3-substituted 3-amino-2-oxindole derivatives.
However, the enantioselective allylation of ketimines is
not a trivial task due to their low reactivity and the difficulty
in controlling enantiofacial aspects.[7] Pioneering work on
the catalytic enantioselective allylation of various ketimines
has been reported by Shibasaki and co-workers in which the
reaction of various acyclic ketimines with allylboronate by
using {Duphos–CuF} catalyst gave products in high yield
with high enantioselectivity.[7a] Recently, Lam and co-work-
ers reported the catalytic enantioselective allylation of cyclic
ketimines by using chiral rhodium complexes.[7b] Despite the
fact that electron-deficient ketimines derived from isatins
would constitute an elegant precursor of biologically active
compounds and quaternary a-amino acids, the catalytic
Entry
1
Catalyst
t [h]
Yield [%]
ee [%][a]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1c
1c
1c
3a
3b
3c
3d
3e
3 f
3g
3h
3h
3h
3h
3h
3h
3h
36
36
24
36
72
36
24
24
24
24
24
72
36
54
91
87
90
92
82
92
93
92
93
91
88
68
92
93
71 (S)
7 (S)
57 (R)
62 (R)
7 (R)
72 (S)
78 (S)
85 (S)
81 (S)
92 (S)
0
9
[a] Prof. S. Nakamura, K. Hyodo, M. Nakamura, Dr. D. Nakane,
Prof. H. Masuda
10
11
12[b]
13[c]
14[d]
Department of Frontier Materials, Graduate School of Engineering
Nagoya Institute of Technology
Gokiso, Showa-ku, Nagoya 466-8555 (Japan)
Fax : (+81)52-735-5245
66 (S)
94 (S)
90 (S)
E-mail: snakamur@nitech.ac.jp
[a] The absolute configuration of 2 is provided in parentheses. [b] Allyl-
trimethylsilane was used. [c] The reaction was carried out at À308C.
[d] Catalyst (1 mol%) was used.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300685.
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www.chemeurj.org
7305

S. Nakamura et al.
The reaction of ketimine 1a derived from N-benzylisatin
with allyltrimethoxysilane by using N-benzoylated palladium
pincer-type catalyst 3a afforded product 2a in high yield
with moderate enantioselectivity (Table 1, entry 1).[15] En-
couraged by this result, we next investigated the effect of
the catalyst structure on stereoselectivity. The reaction of 1a
with allylsilane by using acetylated catalyst 3b gave product
2a as an almost racemic product (entry 2). Interestingly, the
reaction using sulfonylated catalysts 3c and 3d afforded 2a
containing a stereochemistry opposite that obtained in the
reaction using 3a (entries 3 and 4). The reaction using cata-
lysts 3 f,g containing electron-donating groups on the benzo-
yl group afforded product 2a with high enantioselectivity
(entries 6 and 7). When catalyst 3h, containing a tert-butyl
group on the phenylene linker, was used, to our delight,
good enantioselectivity was obtained (entry 8). To improve
enantioselectivity, we optimized the structure of ketimines
derived from isatins containing various protecting groups
on the nitrogen atom (entries 9–11). When the reaction
with ketimine 1c, containing a triphenylmethyl group (trityl
group: Tr), was carried out, enantioselectivity could be im-
proved (entry 10). The reaction of 1c with allyltrimethylsi-
lane as an allylating reagent afforded the product 2c in
moderate yield with moderate enantioselectivity (entry 12).
The reaction at lower temperature (À308C) allowed for
even more rigorous enantiofacial control (entry 13). Even
1 mol% of 3h worked efficiently (entry 14).
Scheme 1. Reaction of ketimine 1c with 2-substituted allylsilane.
We next examined the synthesis of optically active homo-
allylamine 4 from N-tert-butoxycarbonyl-N’-trityl-protected
amide 2k (Scheme 2). Deprotection of both the tert-butoxy-
carbonyl (Boc) and trityl (Tr) group from 93% ee of 2k by
Scheme 2. Transformation of products to chiral homoallylic amines or a
spiroamine.
With these optimized conditions, the allylation of a series
of ketimines 1c,e–n with 3h and AgF was examined
(Table 2). Ketimines 1e–n carrying either electron-donating
using trifluoroacetic acid in 1,2-dichloroethane at 508C af-
forded homoallylic amine 4 in high yield without a loss of
enantiopurity. The absolute configuration of 4 was assigned
as S by X-ray crystallographic analysis, and the configura-
tion of other products was tentatively assumed by analogy.
We next examined the formation of a spirocyclic compound
from the product. The N-allylation of 2c by using allylbro-
mide, sodium hydride, and tetrabutylammonium bromide
(TBAB) in DMF afforded N-allyl-N-Boc product 5 in high
yield. The ring-closing metathesis of 5 by using a second
generation of Grubbs catalyst in toluene gave spirocyclic
amine 6 in high yield.
The proposed catalytic cycle for the allylation of keti-
mines derived from isatins is shown in Figure 3. The addi-
tion of AgF causes the exchange reaction of bromide in 3 to
fluoride (complex A). The fluoride on palladium reacts with
allylsilane to give an h1-allyl coordinated pincer species
(complex B). The next step is the nucleophilic reaction of
allyl-palladium species with ketimines to give complex C,
which subsequently undergoes transmetallation with silver
fluoride giving product 2.[16] To clarify the assumed catalytic
cycle, we conducted spectroscopic analysis. The ESI mass
spectrometric analysis of the mixture of 3b, AgF, and allyl-
trimethoxysilane in a 1:1:1 ratio in THF showed complex B
(cation mode, calcd for C53H43N4O2Pd as complex B+H+:
873.2; found: 873.0, see the Supporting Information). These
signals support our proposed catalytic cycle.
Table 2. Enantioselective allylation of ketimines 1c,e–n by using 3h.
Entry
R
2
t [h]
Yield [%]
ee [%]
1[a]
2
3
4
5
H (1c)
2c
2e
2 f
2g
2h
2i
2j
2k
2l
72
36
48
60
48
72
24
48
36
48
48
92
91
92
92
96
84
94
93
93
95
90
95
94
90
91
85
82
85
93
93
93
87
5-Me (1e)
5-MeO (1 f)
5-F (1g)
5-Cl (1h)
5-Br (1i)
4-Br (1j)
6-Br (1k)
6-Cl (1l)
7-F (1m)
4,6-Me (1n)
6
7[a]
8
9
10
11
2m
2n
[a] The reaction was carried out at À408C.
or -withdrawing substituents gave products 3e–n in good
yield with high enantioselectivity (entries 2–10).
We also examined the reaction with 2-substituted allyltri-
methoxysilane. The reaction afforded product 2o in high
yield with good enantioselectivity (Scheme 1).
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Catalytic Enantioselective Allylation of Ketimines
COMMUNICATION
allyl group on palladium attacks
imines at the g-position of the
allyl moiety without coordina-
tion to sulfonylimines. There-
fore, we tried to check the
structure of allylpalladium com-
plex B by the MO calculation
by using Gaussian 09[17] B3LYP/
LANL2DZ level[18] (Figure 5).
To simplify the calculation, bi-
s(imidazoline) 3a was used to
optimize the complex. The allyl
moiety coordinates to palladi-
um avoiding steric repulsion
with the bulky phenyl groups in
3a. Based on the structure of
the palladium pincer complexes
and the absolute configuration
of products, Figure 5 shows a
proposed transition state for
the enantioselective allylation
of imine by using 3a. Imine 1
approaches from the opposite
Figure 3. Plausible catalytic cycle for the reaction.
À
side of the Pd C bond. Avoid-
ing steric repulsion of the trityl group in ketimines with the
phenyl group in chiral bis(imidazoline) and electrostatic re-
pulsion of the allyl group on palladium with carbonyl and
imino groups in ketimine, the Re face of ketimine reacts
with allylpalladium to give the S isomer. Further studies are
required to fully elucidate the mechanistic detail of the ally-
lation of imines.[19,20]
In conclusion, we developed an enantioselective allylation
of ketimines derived from isatins by using chiral palladium
pincer complexes between 1,3-bis(imidazolin-2-yl)benzene
to give products with good enantioselectivity. This process
offers a simple and efficient route for the synthesis of a ho-
moallylic amine containing a tetrasubstituted stereocenter
and its derivatives. Further experiments are in progress to
study the scope of this process and the potential application
of the bis(imidazoline)–palladium pincer catalyst to other
reactions.
Figure 4. X-ray crystal structure of 3h·CHCl3 (top view (a), side
view (b)). H atoms and chloroform have been omitted for clarity.
Experimental Section
Typical procedure for allylation of ketimines catalyzed by chiral Phebim–
PdII complexes
We also confirmed the structures of the palladium pincer
complex 3h by X-ray crystallographic analysis (Figure 4).
The bis(imidazoline) ligand is coordinated to the PdII center
by two nitrogen atoms in imidazoline and one carbon atom
in the aryl group in a tridentate manner. Complex 3h fea-
tures a nearly square-planar PdII center in which the five
rings include two imidazolines, two palladacycles, and ben-
zene, which are approximately coplanar.
tert-Butyl 3-(2-propenyl)-1-(triphenylmethyl)-2-oxoindolin-3-ylcarbamate
(2c): A mixture of 3h (4.5 mg, 3.9 mmol), and AgF (10.0 mg, 0.079 mmol)
was stirred in THF for 1 h. After the addition of 1c (38.5 mg,
0.079 mmol), the reaction mixture was cooled to À308C. Then, allyltrime-
thoxysilane (26.6 mL, 0.158 mmol) was added. After the disappearance of
1c in the reaction mixture on TLC, water (0.5 mL) was added. The mix-
ture was filtered through Celite to remove silver salts and the filtrate was
extracted with CH2Cl2. The combined organic layer was dried over
Na2SO4. Removal of solvent under reduced pressure gave a residue,
which was purified by column chromatography (hexane/ethyl acetate
90:10) to give (S)-2c (38.5 mg, 92%) as a white solid.
Based on a previous DFT study on the achiral pincer-
complex-catalyzed allylation of sulfonylimines,[14kl,m] the h1-
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S. Nakamura et al.
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Acknowledgements
This work was supported by the Teijin Pharma Award in Synthetic Or-
ganic Chemistry, Japan and a Sasagawa Scientific Research Grant from
the Japan Science Society. We thank Prof. N. Shibata at the Nagoya Insti-
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Keywords: allylation · asymmetric catalysis · ketimines ·
palladium · pincer complexes
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Catalytic Enantioselective Allylation of Ketimines
COMMUNICATION
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trimethoxysilane to give the product and complex B.
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[20] The origin of the reversed stereochemistry obtained from the reac-
tion using 3a or 3c is unclear. However, it is known that the nitro-
gen of N-sulfonylimidazoline takes the pyramidal structure, whereas
N-benzoylimidazolines have planar nitrogen atoms. There is a possi-
bility that the drastic change of the nitrogen structure in bis(imida-
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needed to prove the above assumed transition state. See also, S.
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[14] Szabꢂ and co-workers have reported the enantioselective allylation
of aldimines with allylstannane by using a palladium PCP-pincer
Received: February 21, 2013
Published online: April 30, 2013
Chem. Eur. J. 2013, 19, 7304 – 7309
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7309