Mg-catalyzed enantioselective benzylic C-H bond functionalization of isoindolinones: Addition to imines

Article abstract of DOI:10.1002/chem.201200821

Access to chiral isoindolinones: The Mg-catalyzed enantioselective benzylic CH bond functionalization of isoindolinones is described. A Bu2Mg/Schiff base catalyst (1:1) promoted the enantioselective addition of N-Boc-isoindolinones to aryl, heteroaryl, alkenyl, and alkyl imines, giving 3-substituted isoindolinones in 84-99 % ee and 50:50-91:9 d.r. (see scheme).

Full text of DOI:10.1002/chem.201200821

DOI: 10.1002/chem.201200821
À
Mg-Catalyzed Enantioselective Benzylic C H Bond Functionalization of
Isoindolinones: Addition to Imines
Yudai Suzuki,[a] Motomu Kanai,*[a, b] and Shigeki Matsunaga*[a, b]
Dedicated to Professor Masakatsu Shibasaki on the occasion of his 65th birthday
Isoindolinones are an important structural motif in natu-
ral products and biologically active compounds.[1] Among
them, chiral isoindolinones that bear a carbon substituent at
the C3-position are particularly attractive in medicinal
chemistry, because of their usefulness in many drug candi-
dates, such as pazinaclone 1a (an anxiolytic agent),[2a] cyclin-
dependent kinase 1,2,4,6 inhibitor 1b,[2b] PD172938 1c (a
dopamine D4 receptor antagonist),[2c] and HIV-reverse tran-
scriptase inhibitor 1d (Figure 1).[2d] Although several syn-
thetic methods for chiral 3-substituted isoindolinones have
been reported over the past two decades, most of them are
diastereoselective reactions by using stoichiometric amounts
of chiral auxiliaries or chiral starting materials,[3] and the de-
velopment of catalytic asymmetric methods is in high
demand. Quite recently, a few catalytic asymmetric ap-
proaches have been reported.[4–6] Huang and co-workers re-
ported a catalytic asymmetric tandem Michael/Mannich/cyc-
lization reaction of Et2Zn, chalcone derivatives, and an
imine (methyl 2-[(tosylimino)methyl]benzoate) to form iso-
indolinone cores.[4] Wang et al.[5] and Zhou et al.[6] developed
more straightforward approaches by using 3-hydroxy-substi-
tuted isoindolinones. A chiral Brønsted acid catalyst gener-
ated N-acyliminium intermediates in situ, and an asymmet-
ric Friedel–Crafts reaction with indoles[5] and a reduction
with a Hantzsch ester[6] gave chiral 3-substituted isoindoli-
nones. In these methods, the isoindolinone cores were used
as electrophiles. The use of isoindolinones as nucleophiles
via carbanion formation is an alternative approach for chiral
3-substituted isoindolinones, but only chiral-auxiliary-based
methods by using stoichiometric amounts of strong bases,
such as sodium hexamethyl disilazide (NaHMDS) and lithi-
um diisopropylamide (LDA), have been reported.[7] In strik-
ing contrast to the well-established catalytic asymmetric
methods by using oxindoles as nucleophiles,[8,9] there are no
reports of catalytic nucleophile formation directly from an
isoindolinone core and catalytic asymmetric reactions by
using isoindolinones as nucleophiles, possibly owing to the
lower acidity of the benzylic proton in isoindolidinones than
in oxindoles. Herein, we report the first catalytic enantiose-
Figure 1. Structures of biologically active compounds with 3-substituted
isoindolinone core.
À
lective C H bond functionalization of isoindolinones. A
Bu2Mg/Schiff base 2 catalyst (1:1; Figure 2) promoted the
enantioselective addition of N-Boc-isoindolinones 3 to 2-thi-
ophenesulfonyl imines 4, giving 3-substituted functionalized
isoindolinones in up to 98% ee and 91:9 d.r.
[a] Y. Suzuki, Prof. Dr. M. Kanai, Dr. S. Matsunaga
Graduate School of Pharmaceutical Sciences
The University of Tokyo
À
To realize catalytic benzylic C H bond functionaliza-
tion,[10] we screened various metal and ligand combinations
by using N-Boc-isoindolinone (3a) and 2-thiophenesulfonyl
imine 4a[11,12] as model substrates. Among the ligands
screened, Schiff base ligand 2a afforded promising re-
sults.[13–15] The results of the optimization studies by using
Schiff base ligands are summarized in Table 1. Because rare
earth metal alkoxides failed to promote the reaction (en-
tries 1 and 2), we screened more Brønsted basic Group 2
metal sources (entries 3–6). Although Group 2 metal alkox-
ides did not promote the reaction (entries 3–5),[16] a Bu2Mg/
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax : (+81)3-5684-5206
E-mail: kanai@mol.f.u-tokyo.ac.jp
smatsuna@mol.f.u-tokyo.ac.jp
[b] Prof. Dr. M. Kanai, Dr. S. Matsunaga
Kanai Life Science Catalysis Project, ERATO
Japan Science and Technology Agency
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200821.
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Chem. Eur. J. 2012, 18, 7654 – 7657

COMMUNICATION
The substrate scope and limitations of the Mg-catalyzed
enantioselective addition of isoindolinones 3 to imines are
summarized in Table 2. To simplify the purification process
by silica gel column chromatography, the isolated yield
(Table 2) was determined after removing the Boc group by
treatment with TFA (trifluoroacetic acid). With isoindoli-
none 3a and imine 4a, the catalyst loading was successfully
reduced to 5 mol%, and good yield and stereoselectivity
were maintained (entry 2). With 2.5 mol% catalyst, the re-
action was not complete, even after 72 h (entry 3). Isoindoli-
nones 3b and 3c bearing an electron-donating group at the
C6-position (Figure 2) gave products with excellent enantio-
selectivity (entries 4 and 5). The substituent at the C4-posi-
tion of the isoindolinone core, which is close to the reaction
site, was also compatible, and isoindolinone 3d gave syn-
6da in 91% ee (entry 6). The diastereoselectivity with 3d,
however, was slightly decreased. Next, the imine scope was
investigated (entries 7–14). An electron-donating substituent
at the para position of the imineꢁs aromatic ring in 4c and
4d was compatible, giving products in 83:17 and 78:22 d.r.
and 97 and 95% ee, respectively (entries 8 and 9). The dia-
stereoselectivity strongly depended on the imine structure,
and imines 4e–h resulted in poor to moderate diastereose-
lectivity, while high enantioselectivity was observed for all
entries (entries 10–13). It is worth noting that the present
system was applicable to enolizable alkyl imines, and imine
4i gave product 6ai in high yield, diastereoselectivity, and
enantioselectivity (entry 14). The result in entry 14 suggests
that the Mg-catalyst chemoselectively activates the benzylic
Figure 2. Structures of Schiff bases 2a–e, N-Boc-isoindolinones 3a–d, and
2-thiophenesulfonyl imines 4.
Table 1. Optimization studies.
Entry
Metal
Ligand
Yield [%][a]
d.r.[b]
(syn/anti)
ee [%][c]
ACHTUNGTNER(NUNG syn)
U
1
2
3
4
5
6
7
8
9
La
Sc(OiPr)2
Ba(OiPr)2
Sr(OiPr)2
Mg(OiPr)2
Bu2Mg
Et2Zn
Bu2Mg
Bu2Mg
Bu2Mg
Bu2Mg
G
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
0
0
0
0
0
–
–
–
–
n.d.
n.d.
n.d.
n.d.
n.d.
88
n.d.
n.d.
n.d.
83
À
C H bond of isoindolinone 3a, while isomerization of imine
G
4i to the enamide was suppressed. For imines affording
moderate diastereoselectivity, the enantiomeric excess of
both isomers was determined, and both isomers gave good
to high enantioselectivity (84–98% ee; entries 10–13 in pa-
rentheses). The absolute configuration of both diastereo-
mers was unequivocally determined by X-ray crystallograph-
ic analysis (Figure 3).[17] The results suggest that the catalyst
clearly differentiates the enantiofacial selectivity of the iso-
indolinones, giving both diastereomers in high enantioselec-
G
–
40
0
0
0
14
>95
86:14
–
–
–
10
11
86:14
86:14
98
1
[a] Determined by H NMR analysis with an internal standard. [b] Deter-
1
mined by H NMR analysis of the crude mixture. [c] Enantiomeric excess
was determined by HPLC analysis using a chiral stationary phase after
removal of the Boc group. n.d.=not determined.
Schiff base 2a complex (1:1) promoted the addition of 3a to
4a, giving product 5aa in 40% yield, 86:14 d.r., and 88% ee
after 10 h (entry 6). No reaction occurred when using anoth-
er alkyl metal source, Et2Zn (entry 7). The MeO group in
Schiff base 2 was critical for both reactivity and selectivity,
and Schiff bases 2b, c, and d resulted in poor reactivity (en-
tries 8–10). On the other hand, Schiff base 2e with addition-
al MeO groups gave much higher reactivity than 2a, possi-
bly owing to a difference in the Brønsted basicity of the Mg-
aryloxide species. The enantioselectivity also improved with
2e, and a Bu2Mg/Schiff base 2e catalyst (1:1) gave product
5aa in >95% yield, 86:14 d.r., and 98% ee after 10 h
(entry 11).
Figure 3. ORTEP plots of syn-5af and anti-5ae.
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7655

M. Kanai, S. Matsunaga, and Y. Suzuki
Table 2. Mg-catalyzed enantioselective addition of isoindolinones 3 to imines 4.[a]
and diluted with AcOEt. The diastereoselectivity was deter-
mined by 1H NMR analysis of the crude mixture at this stage.
After evaporation, the residue was dissolved in CH2Cl2
(2.0 mL) and TFA (5 equiv) was added at 08C. The resulting
mixture was stirred at RT for 3 h. After evaporation, the crude
mixture was purified by flash silica gel column chromatogra-
phy (AcOEt/hexane) to afford 6. The ee value of 6 was deter-
mined by HPLC analysis using a chiral stationary phase.
Acknowledgements
Entry
3
R
4
6
Cat.
A
t
Yield d.r.[c]
(syn/anti)
ee [%][d]
(syn)
[mol%] [h] [%][b]
N
ACHTUNGTRENNUNG
We thank Dr. H. Sato at RIGAKU for technical support on
X-ray analysis. This work was supported by a Grant-in-Aid for
Scientific Research on Innovative Areas “Molecular Activa-
tion Directed toward Straightforward Synthesis” from MEXT,
ERATO from JST, Grant-in-Aid for Young Scientist (A) from
JSPS, Inoue Foundation for Science, and the Naito Founda-
tion.
1
2
3a 4-BrC6H4
3a 4-BrC6H4
3a 4-BrC6H4
3b 4-BrC6H4
3c 4-BrC6H4
3d 4-BrC6H4
3a 4-PhC6H4
3a 4-MeOC6H4
3a 4-MeC6H4
3a 2-MeC6H4
3a 2-naphthyl
3a 2-thienyl
4a 6aa 10
10 95
36 94
72 76
24 90
48 77
24 78
12 86
24 95
12 86
12 95
12 87
12 83
24 64
24 90
86:14
82:18
83:17
82:18
80:20
76:24
79:21
83:17
78:22
50:50
58:42
61:39
64:36
91:9
98
97
99
97
97
91
97
97
4a 6aa
4a 6aa
5
2.5
3[e]
4
4a 6ba 10
4a 6ca 10
4a 6da 10
4b 6ab 10
4c 6ac 10
4d 6ad 10
4e 6ae 10
4 f 6af 10
4g 6ag 10
5
6
7
8
9
95
À
Keywords: asymmetric catalysis · C H activation ·
imines · isoindolinones · magnesium
10
11
12
13
14
98(97)[f]
97(98)[f]
96(95)[f]
93(84)[f]
92
3a (E)-PhCH=CH 4h 6ah 10
3a cyclohexyl 4i 6ai 10
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[a] Reaction was run by using isoindolinone 3 (0.20 mmol), imine 4 in THF (1.1 equiv,
0.50m), Bu2Mg (10 mol%), and Schiff base 2e (10 mol%) with MS 5 ꢂ (17.2 mg),
unless otherwise noted. [b] Isolated yield of 6 in two steps after purification by silica
1
gel column chromatography. [c] Determined by H NMR analysis of the crude mixture
of 5 after the addition to imine 4. [d] Determined by HPLC analysis using a chiral sta-
tionary phase. [e] Reaction was run by using isoindolinone 3a (0.4 mmol). [f] The
value in parenthesis is the enantiomeric excess of anti-6.
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In summary, we developed a Mg-catalyzed enantioselec-
À
tive benzylic C H bond functionalization of isoindolinones.
A Bu2Mg/Schiff base catalyst (1:1) promoted the enantiose-
lective addition of N-Boc-isoindolinones to aryl, heteroaryl,
alkenyl, and enolizable alkyl imines, giving 3-substituted iso-
indolinones in 84–99% ee and 50:50–91:9 d.r. In comparison
with previous methods,[4–6] the present method provides
a complementary catalytic asymmetric access to chiral isoin-
dolinones. Trials to improve the diastereoselectivity through
ligand modifications and applications of the present method
for the design and synthesis of biologically active com-
pounds are ongoing.
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Experimental Section
A test tube charged with MS 5 ꢂ (17.2 mg) was flame dried under re-
duced pressure (around 1.0 kPa). After cooling down to RT, argon was
refilled and (R)-2e (12.3 mg, 0.020 mmol), THF (0.47 mL), and then
Bu2Mg (1.0m in heptane, 20 mL, 0.020 mmol) were added. After stirring
for 30 min at RT, THF was removed under reduced pressure and N-Boc-
isoindolinone 3 (0.20 mmol), imine 4 (0.22 mmol, 1.1 equiv), and THF
(0.40 mL) were added to the test tube. The resulting mixture was stirred
at RT for the indicated time (Table 2) and quenched by adding silica gel
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À
Mg-Catalyzed Enantioselective C H Bond Functionalization
COMMUNICATION
(LDA=lithium diisopropylamide), see: d) A. Couture, E. Deniau, P.
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[12] Other imines, such as Ts-imine (Ts=p-toluenesulfonyl), 2-pyridine-
sulfonyl imine, diphenylphosphinoyl imine, and Boc-imine resulted
in much less satisfactory yield and/or enantioselectivity when using
Bu2Mg/Schiff base catalysts.
[13] For the utility of MeO-substituted Schiff base 2a and related ligands
in asymmetric catalysis, see: a) B. Wu, J. C. Gallucci, J. R. Parquette,
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[15] Other chiral ligands, such as BINOL derivatives (BINOL=1,1ꢁ-bi-2-
naphthol) and chiral bis-sulfonamides, resulted in poor reactivity
and/or stereoselectivity.
[16] The difference in reactivity between Mg-alkoxide and dialkyl mag-
nesium can be ascribed to the difference in solubility under the reac-
tion conditions.
[17] CCDC-870068 (syn-5af) and CCDC-870069 (anti-5ae) contain the
supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[18] Because the structure of the catalyst, prepared from Bu2Mg/Schiff
base 2 (Figure 2) in a ratio of 1:1, has not been clarified, it is diffi-
cult to propose the transition state model to explain the stereochem-
istry of products. The Bu2Mg/Schiff base 2 1:1 mixture is speculated
to have an oligomeric structure, see ref. [14b].
À
asymmetric C C bond formation, see: b) B. M. Trost, J. Xie, J. D.
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Received: March 11, 2012
Published online: May 21, 2012
Chem. Eur. J. 2012, 18, 7654 – 7657
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7657