Hydroxorhodium/chiral diene complexes as effective catalysts for the asymmetric arylation of 3-aryl-3-hydroxyisoindolin-1-ones

Article abstract of DOI:10.1002/anie.201208593

Water is out, aryl is in! Asymmetric synthesis of isoindoline-1-ones bearing an α-triaryl-substituted stereogenic center was realized in the enantioselective addition of arylboroxines to 3-aryl-3-hydroxyisoindolin-1-ones in the presence of a hydroxorhodium/chiral diene catalyst, where cyclic N-carbonyl ketimines were generated in situ by dehydration. Copyright

Full text of DOI:10.1002/anie.201208593

Angewandte
Chemie
DOI: 10.1002/anie.201208593
Asymmetric Arylation
Hydroxorhodium/Chiral Diene Complexes as Effective Catalysts for
the Asymmetric Arylation of 3-Aryl-3-hydroxyisoindolin-1-ones**
Takahiro Nishimura,* Akira Noishiki, Yusuke Ebe, and Tamio Hayashi*
The transition-metal-catalyzed enantioselective alkylation
and arylation of imines is a versatile means of accessing
a-chiral amines, which are important structural components
of a number of biologically active compounds, and there have
been many reports of the successful catalytic enantioselective
addition of organometallic reagents to imines derived from
aldehydes.[1] In contrast, the asymmetric addition of organo-
metallic reagents to ketimines, which provides chiral
a-tertiary amines, remains less developed.[2–4] In this context,
we have reported that rhodium/chiral diene complexes
efficiently catalyze the asymmetric addition of arylboron
reagents to N-sulfonyl ketimines with high enantioselectiv-
ity.[5,6] Herein, we report the rhodium-catalyzed asymmetric
arylation of cyclic N-carbonyl ketimines, which are generated
in situ by the dehydration of 3-aryl-3-hydroxyisoindolin-1-
ones with arylboroxines, resulting in isoindolin-1-ones bear-
ing a triaryl-substituted stereogenic carbon center.
The stability of imines towards hydrolysis depends on the
substituent on the imine nitrogen. For example, N-sulfonyl
imines are sufficiently stable to be isolated and they are often
used in the addition of organometallic reagents. On the other
hand, when the imines are highly sensitive to hydrolysis,
benzotriazole[7] or sulfinic acid imine adducts,[8] or hemi-
aminals[9b] have been often used as stable imine precursors.
We focused on the use of 3-aryl-3-hydroxyisoindolin-1-ones[9]
1 as stable precursors for the generation of cyclic N-carbonyl
ketimines bearing a diaryl-substituted azomethine moiety,
which can be used in the rhodium-catalyzed asymmetric
arylation reaction to produce chiral isoindolin-1-ones, which
are structurally important core unit found in many biologi-
cally active compounds and natural products (Scheme 1).[10,11]
We also decided to use arylboroxines 2, which are dehydrated
analogues of arylboronic acids, because they would be
expected to work as dehydrating reagents to generate
ketimine A, as well as arylating reagents for a subsequent
arylation by a rhodium catalyst.
Scheme 1. Asymmetric arylation of isoindolin-1-ones 1.
It was found that a hydroxorhodium complex was
effective in catalyzing the arylation of 3-phenyl-3-hydroxy-
isoindolin-1-one (1a) with arylboroxines 2 (Table 1). Thus,
treatment of hemiaminal 1a with p-tolylboroxine (2m;
2 equiv of B) in the presence of a hydroxorhodium complex
[{Rh(OH)(cod)}2] (5 mol% of Rh; cod = 1,5-cyclooctadiene)
at 808C for 12 h gave 3-phenyl-3-(p-tolyl)isoindolin-1-one
(3am) in 87% yield (entry 1). The arylating reagent
p-tolylboronate 2m’ is also effective, giving 3am in 85%
Table 1: Rhodium-catalyzed asymmetric arylation of 3-hydroxyisoindolin-
1-one 1a.[a]
Entry
Catalyst
p-tol[B]
Yield [%][b]
ee [%][b]
1
2
3
[{Rh(OH)(cod)}2]
[{Rh(OH)(cod)}2]
[{Rh(OH)(cod)}2]
[{RhCl(cod)}2]/KOH (aq)
[{RhCl(cod)}2]/K3PO4
[{Rh(OH)[(R,R)-Bn-tfb*]}2]
[{Rh(OH)[(R,R)-Ph-tfb*]}2]
[{Rh(OH)[(S,S)-Fc-tfb*]}2]
[{Rh(OH)[(S,S)-Fc-tfb*]}2]
[{Rh(OH)[(R)-binap]}2]
2m
2m’
2m’’
2m
2m
2m
2m
2m
2m
2m
87
85
7
0
7
50
79
90[e]
96[e]
44
–
–
–
–
4[c]
5[d]
6
–
33
87
95
95
63
7
8
9[f]
10
[*] Dr. T. Nishimura, A. Noishiki, Y. Ebe
[a] Reaction conditions: 1a (0.10 mmol), p-tol[B] 2 (0.20 mmol of B),
rhodium catalyst (5 mol% of Rh), 1,4-dioxane (0.4 mL) at 808C for 12 h.
[b] Yield of 3am determined by 1H NMR spectroscopy. [c] Performed
with aq. KOH (1m, 20 mol%). [d] Performed with K3PO4 (1 equiv).
[e] Yield of isolated product. [f] Performed with 0.083 mmol of 2m
(2.5 equiv of B) for 24 h.
Department of Chemistry, Graduate School of Science, Kyoto
University, Sakyo, Kyoto 606-8502 (Japan)
E-mail: tnishi@kuchem.kyoto-u.ac.jp
Prof. Dr. T. Hayashi
Institute of Materials Research and Engineering
A*STAR, 3 Research Link, Singapore 117602 (Singapore)
E-mail: tamioh@imre.a-star.edu.sg
[**] This work was supported by a Grant-in-Aid for Scientific Research
from the MEXT (Japan).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201208593.
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Table 2: Rhodium-catalyzed asymmetric arylation of 3-hydroxyisoindo-
lin-1-ones 1.[a]
yield (entry 2). In sharp contrast, the reaction of 1a with p-
tolylboronic acid (2m’’) gave only 7% yield of 3am, although
the formation of imines from 3-hydroxyisoindolin-1-ones has
been reported to be accelerated by
a Brønsted acid
(entry 3).[9] The low yield of product 3am when p-tolylboronic
acid is used is probably due to the faster hydrolysis of a
p-tolylrhodium intermediate, which leads to toluene rather
than reaction with the imine. The combined use of a chloro-
rhodium complex [{RhCl(cod)}2] and bases such as KOH and
K3PO4, which are often used in the rhodium-catalyzed
addition of arylboron reagents,[12] provided very low catalytic
activity in the present arylation; this was probably due to
inhibition of imine formation by the bases (entries 4 and 5).
These results prompted us to use hydroxorhodium catalysts
coordinated with chiral diene ligands[13] for the development
of an asymmetric variant of the present arylation. We have
recently developed stable hydroxorhodium complexes coor-
dinated with chiral tetrafluorobenzobarrelene (tfb*)
ligands,[14] and thus they were tested in the reaction of 1a
(entries 6–8). The substituents on the tfb ligands significantly
affected the catalytic activity and enantioselectivity. The use
of benzyl-substituted tfb (Bn-tfb*) gave 50% yield of 3am
with 33% ee (entry 6). Higher catalytic activity was observed
for phenyl-substituted tfb (Ph-tfb*), which gave 3am in 79%
yield with 87% ee (entry 7). The ligand Fc-tfb*, which is
substituted with ferrocenyl groups, displayed the highest
enantioselectivity (95% ee) and gave 3am in 90% yield
(entry 8), and in a reaction with 2m (2.5 equiv of B) for
a prolonged reaction time (24 h) it gave 3am in 96% yield
with 95% ee (entry 9). The same reaction was also catalyzed
by a hydroxorhodium complex coordinated with (R)-binap,
which is one of the most active catalysts for the 1,4-addition of
arylboronic acids,[15] but the yield and ee of 3am was only
moderate (44% yield, 63% ee; entry 10).
Entry
Product
Ar1 or Ar2
Yield ee
[%][b] [%][c]
1
2
3
4
5
6
7
3am: Ar2 =4-MeC6H4
3an: Ar2 =3-MeC6H4
3ao: Ar2 =2-MeC6H4
3ap: Ar2 =4-MeOC6H4
98
99
94
94
95
95
98
94
96
97
96
97
97
3aq: Ar2 =3,4-(OCH2O)C6H3 93
3ar: Ar2 =2-naphthyl
3as: Ar2 =4-FC6H4
3at: Ar2 =4-ClC6H4
3au: Ar2 =4-CF3C6H4
91
87
98
96
8[d]
9[d]
10
3bv: Ar1 =4-MeC6H4
95
94
11
12
13
14
15[d]
16
17
3 cm: Ar1 =3-MeC6H4
3dm: Ar1 =4-MeOC6H4
3em: Ar1 =2-MeOC6H4
3 fm: Ar1 =4-ClC6H4
3gm: Ar1 =4-CF3C6H4
3hm: Ar1 =2-furyl
94
99
94
82
65
87
89
95
97
98
94
91
96
93
3im: Ar1 =2-thienyl
18
19
3jm: X=6-MeO
3km: X=5-MeO
89
89
95
95
3 fr: Ar1 =4-ClC6H4
Ar2 =2-naphthyl
3 fo: Ar1 =4-ClC6H4
Ar2 =2-MeC6H4
20
21
95
82
96
98
Table 2 summarizes the results obtained for the reaction
of 3-aryl-3-hydroxyisoindolin-1-ones 1 with arylboroxines 2
catalyzed by [{Rh(OH)[(S,S)-Fc-tfb*]}2]. Aryl groups having
a variety of electron-donating and -withdrawing substituents
at the ortho, meta, and para positions of the phenyl substituent
were successfully introduced onto the azomethine carbon of
1a to give the corresponding addition products 3am–3au in
high yields with over 94% ee (entries 1–9). The present
catalytic system can also be applied to the asymmetric
arylation of several 3-aryl-3-hydroxyisoindoline-1-ones
1 with high enantioselectivity (entries 10–21). The addition
of phenylboroxine (2v) to 1b, which is substituted with a
p-tolyl group, and thus is the reverse of the combination in the
reaction of 1a with 2m, gave the opposite enantiomer ((À)-
3bv) vs. (+)-3am in 95% yield with 94% ee (entry 10). The
addition of p-tolylboroxine (2m) to ketimines 1c–1g, which
possess several aromatic rings substituted with both electron-
donating (Me, MeO) and -withdrawing groups (Cl, CF3)
proceeded to give the corresponding isoindolin-1-ones 3 cm–
3gm with high enantioselectivity (entries 11–15). Substrates
that include heteroaromatic rings, such as 2-furyl (1h) and 2-
thienyl (1i) 3-hydroxyisoindolin-1-ones, are also good sub-
strates and give the corresponding isoindolin-1-ones 3hm and
3im with 96% and 93% ee, respectively (entries 16 and 17).
The present catalytic system provides a general method for
[a] Reaction conditions: 1 (0.20 mmol), 2 (0.17 mmol), [{Rh(OH)[(S,S)-
Fc-tfb*]}2] (5 mol% of Rh), 1,4-dioxane (0.8 mL) at 808C for 24 h.
[b] Yield of isolated product. [c] Determined by HPLC analysis on a chiral
stationary phase. [d] Performed with 0.33 mmol of 2 (5 equiv of B) for
48 h.
the preparation of enantioenriched isoindolin-1-ones substi-
tuted with a variety of aromatic groups (entries 18–21).
The absolute configuration of isoindolin-1-one 3 fo was
determined to be R by X-ray crystallographic analysis of 4,[16]
which was derived from 3 fo in 81% yield without loss in its
enantiomeric purity by treatment with N-bromosuccinimide
(NBS) in the presence of ZrCl4,[17] followed by NaH
(Scheme 2). The absolute configuration is in good agreement
Scheme 2. Transformation of 3 fo into 4. a) N-bromosuccinimide, cat.
ZrCl4. b) NaH.
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addition to N-tosylimines by use of C2-symmetric chiral diene
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In summary, we have developed an asymmetric synthesis
of isoindoline-1-ones bearing an a-triaryl-substituted stereo-
genic center through the enantioselective addition of arylbor-
oxines to 3-hydroxyisoindolin-1-ones catalyzed by a hydroxo-
rhodium/chiral diene complex, wherein cyclic N-carbonyl
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Experimental Section
[{Rh(OH)[(S,S)-Fc-tfb*]}2] (7.1 mg, 0.010 mmol of Rh), 3-hydroxy-3-
phenylisoindolin-1-one (1a; 45.1 mg, 0.200 mmol), and p-tolylborox-
ine (2m; 59.0 mg, 0.167 mmol) were placed in a Schlenk tube under
nitrogen. 1,4-Dioxane (0.80 mL) was added and the mixture was
stirred at 808C for 24 h. The mixture was passed through a short
column of alumina with EtOAc as eluent. The solvent was removed
on a rotary evaporator and the residue was subjected to preparative
TLC on silica gel with EtOAc/n-hexane (1:1) to give 3am (58.5 mg,
0.195 mmol, 98% yield).
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Received: October 25, 2012
Published online: January 10, 2013
Keywords: asymmetric catalysis · chiral dienes ·
.
isoindolin-1-one · rhodium
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