Rhodium-catalyzed asymmetric addition of aryl- and alkenylboronic acids to isatins

Article abstract of DOI:10.1002/anie.200600392

(Chemical Equation Presented) Mopping up the rhodium: A rhodium-catalyzed asymmetric addition of aryl-boronic acids to isatins has been developed to produce biologically relevant 3-aryl-3-hydroxy-2-oxindoles in high yield (see scheme). High enantioselectivity was observed with (R)-MeO-mop as a ligand, and the reaction could be extended to the addition of alkenyl groups.

Full text of DOI:10.1002/anie.200600392

Angewandte
Chemie
Asymmetric Catalysis
DOI: 10.1002/anie.200600392
Rhodium-Catalyzed Asymmetric Addition of
Aryl- and Alkenylboronic Acids to Isatins**
Ryo Shintani, Mitsunori Inoue, and Tamio Hayashi*
Oxindoles constitute a common structural motif in various
natural products and biologically active compounds.[1] Among
them, 3-aryl-3-hydroxy-2-oxindoles are a useful class of
compounds found in several drug candidates.[2–4] For example,
compound A (SM-130686) is a potent growth hormone
secretagogue[2] and compound B shows a high affinity for
the arginine-vasopressin (AVP) V1b receptors and/or the
ocytocin (OT) receptors (Figure 1).[3] Owing to the signifi-
Figure 1. Examples of biologically active 3-aryl-3-hydroxy-2-oxindoles.
cance of this structural motif, the development of a catalytic
asymmetric synthesis of these compounds is highly valuable,
and the asymmetric arylation of isatins would be the most
straightforward approach to this end. To the best of our
[*] Dr. R. Shintani, M. Inoue, Prof. Dr. T. Hayashi
Department of Chemistry
Graduate School of Science
Kyoto University
Sakyo, Kyoto 606-8502 (Japan)
Fax: (+81)75-753-3988
E-mail: thayashi@kuchem.kyoto-u.ac.jp
[**] Support was provided in part by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science,
and Technology, Japan (21 COE on Kyoto University Alliance for
Chemistry).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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knowledge, however, there have been no examples reported
entry 1). Other chiral bis(phosphine) ligands such as (R)-
segphos[13] also turned out to be ineffective in achieving high
enantioselectivity (Table 1, entry 2; 19% ee). We therefore
decided to explore other types of chiral ligands. Unfortu-
nately, the use of (S)-ip-phox,[14] a bidentate P,N ligand, did
not promote this addition reaction (Table 1, entry 3). The
employment of (S)-phosphoramidite[15] or (S)-(R)-ppf-
OMe[16] gave compound 2a, but the enantioselectivity was
still unsatisfactory (Table 1, entries 4 and 5; 39–49% ee). In
contrast, the use of (R)-MeO-mop,[17] an axially chiral mono-
phosphine ligand, gave high yields and significantly improved
the enantioselectivity (Table 1, entry 6; 92% yield, 90%
ee).[18]
to date that employ this strategy.[5,6] Herein, we report that a
Rh/(R)-MeO-mop complex catalyzes the addition of aryl- and
alkenylboronic acids to isatins 1 under mild conditions,
achieving high enantioselectivity [Eq. (1)].[7–10]
Under these conditions with (R)-MeO-mop as a ligand,
various arylboronic acids reacted with isatin 1a to furnish 3-
aryl-3-hydroxy-2-oxindoles 2 in excellent yield and with high
enantioselectivity (Table 2, entries 1–6; 90–98% yield, 82–
91% ee). Although the yield remained high in the addition of
o-tolylboronic acid, a decrease in the ee value was observed
Initially, we conducted a reaction of isatin 1a with
phenylboronic acid in the presence of 5 mol% rhodium
catalyst at 508C to examine the effect of chiral ligands
(Table 1). The use of (R)-binap,[11] which is highly effective for
the rhodium-catalyzed asymmetric addition of arylboronic
acids to various electron-deficient olefins,[12] quantitatively
produced addition product 2a, but with only 24% ee (Table 1,
Table 2: Asymmetric addition of arylboronic acids to isatin 1a catalyzed
by Rh/(R)-MeO-mop.
Table 1: Rhodium-catalyzed asymmetric addition of phenylboronic acid
to isatin 1a.[a]
Entry
1
Product
Yield [%][a]
92
ee [%][b]
Entry
1
Ligand (L)
Yield [%][b] ee [%][c]
2a
2b
90
(R)-binap
100
24 (S)
2
3
4
90
96
95
91
89
82
2
3
4
5
6
(R)-segphos
(S)-ip-phox
80
<2
66
19 (S)
2c
2d
–
(S)-phospor
amidite
39 (S)
49 (R)
90 (S)
5
2e
98
90
(S)-(R)-ppf-OMe
(R)-MeO-mop
43
6
7
2 f
96
93
88
72
92
2g
[a] Rh/L=1:1 (entries 1–3); Rh/L=1:2 (entries 4–6). PMB=p-methoxy-
benzyl. [b] Isolated yield. [c] ee values were determined by HPLC on a
chiralcel OD-H column with hexane/2-propanol (80:20).
[a] Isolated yield. [b] ee values were determined by HPLC on a Chiralcel
OD-H column with hexane/2-propanol (80:20).
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Chemie
(Table 2, entry 7; 93% yield, 72% ee). The absolute config-
urations of these products were assigned as S from X-ray
crystallographic analysis of compound 2e (Figure 2).[19,20]
give tertiary allylic alcohol derivatives in excellent yield and
with high ee values [Eq. (2); 91–98% yield, 88–93% ee].
In summary, we have developed a rhodium-catalyzed
asymmetric addition of arylboronic acids to isatins to produce
biologically relevant 3-aryl-3-hydroxy-2-oxindoles in high
yield. High enantioselectivity was achieved by the use of
(R)-MeO-mop as a ligand, and these conditions can also be
used in the addition of alkenyl groups with high enantiose-
lectivity.
Figure 2. ORTEP illustration of 2e with thermal ellipsoids drawn at the
50% probability level (hydrogen atoms are omitted for clarity).
Experimental Section
General procedure for reactions described in Tables 2 and 3: A
solution of [RhCl(C2H4)2]2 (1.9 mg, 9.8 mmol Rh) and (R)-MeO-mop
(9.4 mg, 20 mmol) in THF (1.0 mL) was stirred for 10 min at room
temperature. KOH (0.10 mL, 30 mmol; 0.3m aqueous), isatin 1
(0.20 mmol), and RB(OH)2 (0.40 mmol) were added successively
with additional THF (1.0 mL), and the resulting mixture was stirred
for 24 h at 508C. The mixture was then directly passed through a pad
of silica gel with Et2O, and after removing the solvent under vacuum,
the residue was purified by preparative thin-layer chromatography on
silica gel with EtOAc/CHCl3 to afford the 1,2-adduct 2.
Moreover, isatins bearing different substituents on the
nitrogen atom and/or the aromatic ring could also be
phenylated effectively under these conditions (Table 3,
entries 1–4; 78–83% yield, 82–89% ee). Even NH isatins
underwent the addition reaction with moderate efficiency
(Table 3, entry 5; 49% yield, 87% ee), in contrast to the
copper-catalyzed N-arylation of NH isatins with arylboronic
acids.[21]
We also found that the Rh/(R)-MeO-mop complex
effectively catalyzes the addition of alkenylboronic acids to
Received: January 30, 2006
Published online: April 5, 2006
Keywords: asymmetric catalysis · boron · isatins · oxindoles ·
rhodium
Table 3: Asymmetric addition of phenylboronic acid to isatins catalyzed
by Rh/(R)-MeO-mop.[a]
.
Entry
Product
Yield [%][b]
ee [%][c]
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Angew. Chem. Int. Ed. 2006, 45, 3353 –3356
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www.angewandte.org
3355

Communications
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