A facile pathway to enantiomerically enriched 3-hydroxy-2-oxindoles: Asymmetric intramolecular arylation of α-keto amides catalyzed by a palladium-DifluorPhos complex

Article abstract of DOI:10.1002/anie.201102158

Less metal wastes: The first catalytic, enantioselective intramolecular aryl-transfer reaction of aryl triflates to ketones has been developed (see scheme; R¹=R²=aromatic and aliphatic). This method features overall practicality, inc

Full text of DOI:10.1002/anie.201102158

Communications
DOI: 10.1002/anie.201102158
Asymmetric Catalysis
A Facile Pathway to Enantiomerically Enriched 3-Hydroxy-2-
Oxindoles: Asymmetric Intramolecular Arylation of a-Keto Amides
Catalyzed by a Palladium–DifluorPhos Complex**
Liang Yin, Motomu Kanai,* and Masakatsu Shibasaki*
Organic group-transfer reactions from halides and triflates to
intermediates for biologically active compounds.[14] Herein,
we report the first example of such a reaction.
We began our study by examining the reaction using a-
keto 2-iodoanilide 1 as a substrate in the presence of (R)-tol-
binap complex of Pd0 as the catalyst (10 mol%) and Et3N as a
reductant (Table 1). Our initial screening of [Pd] sources
ꢀ
carbonyl compounds are a useful C C bond-forming trans-
formation. An example is the chromium-mediated Nozaki–
Hiyama–Kishi (NHK) reaction,[1] whose utility has been
demonstrated by numerous applications to total syntheses of
complex natural products and biologically active com-
pounds.[2] The requirement for stoichiometric amounts of
toxic chromium salts—a major drawback of this reaction—
has been overcome by the use of a catalytic redox system
developed by Fꢀrstner and Shi.[3] This fundamental achieve-
ment allowed for extension to a catalytic enantioselective
variant of the NHK reaction.[4] Despite the great advantages
of the catalytic system compared to the original stoichiomet-
ric system, the requirements for stoichiometric amounts of
Mn0 and TMSCl still conflicts with principles of modern,
Table 1: Optimization of reaction conditions.
environmentally benign synthetic organic chemistry.[5]
A
catalytic asymmetric NHK-type (or Grignard/Barbier-type)
reaction without the use of stoichiometric amounts of metals
is therefore in high demand.
Entry
Substrate
Ligand
t [h]
Yield [%][a]
ee [%][b]
In 2000, Yamamoto and co-workers reported a unique
racemic reaction that would potentially satisfy the above
demand; a palladium-catalyzed intramolecular aryl-transfer
reaction from aryl iodides and bromides to ketones using a
primary alcohol as the stoichiometric reductant.[6] A catalytic
asymmetric variant of this synthetically useful reaction, with
minimal use of metals, has yet to be developed. Combined
with our ongoing interest in the catalytic asymmetric synthesis
of 3-hydroxy-2-oxindoles with an arylic tetrasubstituted
carbon center,[7–12] we began a project to develop a catalytic
enantioselective intramolecular arylation reaction of a-keto
anilides by modifying Yamamotoꢁs original protocol.[13] The
products of this reaction are versatile chiral synthetic
1[c]
1
1
2
3
(R)-tol-binap
(R)-tol-binap
(R)-tol-binap
(R)-tol-binap
(R)-DifluorPhos
(R)-DifluorPhos
(R)-DifluorPhos
(R)-DifluorPhos
(R)-DifluorPhos
12
12
12
12
12
12
24
48
120
15
93
61
68
47
25
87
75
68
8
33
34
78
91
89
91
91
87
2[d]
3[d]
4[d]
5[d]
3
6[d]
4a
4a
4a
4a
7[e,f]
8[e,g]
9[e,h]
[a] Yield of isolated product. [b] Determined by HPLC on a chiral
stationary phase. [c] 1.5 equivalents of Na2CO3 added. [d] 1.5 equivalents
of Ag3PO4 added. [e] In the presence of 2.5 equivalents of Et3N.
[f] 5 mol% of [Pd] and 6 mol% of ligand used. [g] 2.5 mol% of [Pd]
and 3 mol% of ligand used. [h] 1.25 mol% of [Pd] and 1.5 mol% of
ligand used. Bn=benzyl, Tf=trifluoromethanesulfonyl.
[*] Dr. L. Yin, Prof. Dr. M. Kanai
indicated that [Pd(CH3CN)4](BF4)2 was optimal, although the
yield and enantioselectivity were low (Table 1, entry 1).
Based on previous findings in Heck chemistry indicating
that 16-electron species are favored over 18-electron com-
plexes of Pd, we decided to examine the effects of silver salt
additives to generate a cationic 16-electron pretransition-
state intermediate (see 11 in Scheme 3).[15] The addition of
1.5 equivalents of Ag3PO4 improved both yield and enantio-
selectivity, and the product was obtained with 33% ee
(Table 1, entry 2). N-Methyl-substituted substrate 2 afforded
comparable enantioselectivity (Table 1, entry 3). On the other
hand, enantioselectivity was markedly improved using sub-
strate 3 without a protecting group on the nitrogen atom
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo113-0033 (Japan)
Fax: (+81)3-5684-5206
E-mail: kanai@mol.f.u-tokyo.ac.jp
Homepage: http://www.f.u-tokyo.ac.jp/~kanai/index.html
Prof. Dr. M. Shibasaki
Institute of Microbial Chemistry, Tokyo
3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021 (Japan)
E-mail: mshibasa@bikaken.or.jp
[**] Financial support was provided by Grant-in-Aid for Young Scientists
(S) from the JSPS. L.Y. thanks the JSPS for research fellowships.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201102158.
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(78% ee; Table 1, entry 4). Different types of chiral phos-
phines were examined at this stage, and (R)-DifluorPhos[16]
was identified as the best ligand in terms of enantioselectivity
(Table 1, entry 5).[17] To increase the reactivity, aryl triflate 4a
was used as a substrate instead of the iodide. Unfortunately,
product 5a was obtained in only 25% yield (Table 1, entry 6).
Removal of Ag3PO4 and increasing the amount of Et3N to
2.5 equivalents, however, afforded 5a in excellent yield and
high enantioselectivity was maintained (Table 1, entry 7). The
reaction was performed in the presence of 2.5 mol% of [Pd]
and 3 mol% of ligand and afforded the product in slightly
decreased yield and with consistent enantioselectivity
(Table 1, entry 8). Furthermore, catalyst loading could be
decreased to 1.25 mol% to afford a synthetically useful yield
and enantioselectivity, although the reaction time was longer
(Table 1, entry 9).
were tolerated on both of the aromatic rings at the aniline
and ketone sides of the molecule (Table 2, entries 1–11). The
aryl triflate moiety was selectively activated in the presence of
an aryl chloride moiety (Table 2, entry 5), and oxindole 5e
was produced in a synthetically useful yield (63%) with
excellent enantioselectivity (93% ee). Substrates with a
heteroaromatic substituent at the ketone also afforded
excellent results (Table 2, entries 12 and 13). Specifically,
substrate 4m with a non-protected indole and an aryl chloride
moieties produced 5m with 95% ee (Table 2, entry 13). This
reaction was performed in a gram scale and was a key step in
the catalytic enantioselective synthesis of ECi8, which is a
potent antimicrobial lead drug.[18] The synthesis was com-
pleted in four steps from commercially available amino-
phenol 6 (40% overall yield; Scheme 1).[17] The reaction was
Next, the substrate scope was investigated under the
optimized conditions using 5 mol% catalyst (Table 2). Both
electron-donating and electron-withdrawing substituents
Table 2: Catalytic enantioselective intramolecular arylation of a-keto
amides to generate 3-hydroxy-2-oxindoles.
Entry
Product
5a: R1 =H
Yield ee
Scheme 1. Four-step catalytic enantioselective synthesis of ECi8.
[%][a] [%][b]
1
2
3
4
5
6
87
83
92
88
63
87
91[c]
87
90
89
93
82
5b: R1 =5-CH3
5c: R1 =6-CH3
5d: R1 =7-CH3
5e: R1 =6-Cl
also applicable to aliphatic a-keto anilides, and afforded the
corresponding products in high enantioselectivity (Table 2,
entries 14–18). Despite the existence of several catalytic
enantioselective methods for the synthesis of 3-aryl- and 3-
alkenyl-3-hydroxy-2-oxindoles,[7,9b–f,11,12b] the catalytic enan-
tioselective oxidation of indolinones[12a] is the only reported
method generally applicable to the synthesis of the related
compounds substituted with a simple alkane at the 3-position.
Synthesis of the substrates for the catalytic enantioselective
oxidation, however, was not necessarily straightforward.[12a]
Therefore, the current method is noteworthy with regard to
the broad substrate scope, the overall practicality which
includes chemical stability (compared to organometallic
reagents), and the easy accessibility[17] of substrates 4.
Furthermore, the current method is potentially applicable
to the catalytic enantioselective synthesis of 4-hydroxydihy-
droquinolinone derivatives 8 (Scheme 2). Despite their high
synthetic utility as chiral building blocks for drug candi-
dates,[19] there has been no straightforward catalytic asym-
metric route to such compounds. Although enantioselectivity
is still moderate at this stage, a highly hindered tetrasubsti-
tuted carbon center was constructed in a synthetically useful
yield with good enantioselectivity.[17]
5 f: R1 =6-CH3O
7
5g
83
84
8
5h: R3 =2’-CH3
5i: R3 =2’-CH3O
5j: R3 =4’-CH3O
5k: R3 =4’-F
93
92
87
85
90
89
89
99
9[d]
10[d]
11
12
5l
86
71
90
13[e]
5m
95
14
15
16
17
18
5n: R2 =CH3
55
53
74
88[c]
88
83
5o: R2 =CH3CH2
5p: R2 =(CH3)2CH
5q: R2 =(CH3)2CHCH2 82
84
89
2
Finally, a possible catalytic cycle and enantio-differentia-
tion models are proposed in Scheme 3, partly based on
previous reports.[6,20] First, [Pd(CH3CN)4](BF4)2 is reduced by
Et3N in the presence of (R)-DifluorPhos to afford 9.
Subsequently, 9 reacts with the aryl triflate substrate to
afford aryl palladium complex 10, which has six-membered
=
5r: R =(E)-PhCH CH 55
[a] Yield of isolated product. [b] Determined by HPLC on a chiral
stationary phase. [c] Absolute configuration was assigned to be R[17]. For
other entries, the absolute configuration was temporarily assigned based
on analogy to 5a and 5n. [d] Reaction time was 30 h. [e] (S)-DifluorPhos
used.
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Communications
metric reductant and a base, thus eliminating the use of
stoichiometric amounts of metals. Further studies toward
improvement of the 4-hydroxydihydroquinolinone synthesis
as well as expansion of the substrate scope are ongoing.
Experimental Section
General procedure: Complex [Pd(CH3CN)4](BF4)2 (8.9 mg,
0.02 mmol), (R)-DifluorPhos (16.4 mg, 0.024 mmol), and dry toluene
(1.0 mL) were added to a flame-dried flask under argon. The solution
was stirred for 5 min, before dry Et3N (145 mL, 1.0 mmol) and a
solution of aryl triflate 4 (1.0 mL, 0.4 mmol) in toluene were added.
The reaction mixture was then heated at 1008C. After completion of
reaction (as evident by TLC), the mixture was purified by column
chromatography on silica gel (eluent: hexanes/AcOEt = 3/1!1/1) to
afford pure 3-hydroxy-oxindole 5.
Scheme 2. Catalytic enantioselective intramolecular arylation of b-keto
amides to generate 4-hydroxydihydroquinolin-2-one. DEAD=diethyl
azodicarboxylate.
Received: March 28, 2011
Published online: June 1, 2011
Keywords: arylation · asymmetric synthesis · palladium ·
.
synthetic methods · tertiary alcohols
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7622 www.angewandte.org
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