Asymmetric catalytic aza-Morita-Baylis-Hillman reaction for the synthesis of 3-substituted-3-aminooxindoles with chiral quaternary carbon centers

Article abstract of DOI:10.1039/c3ob27495k

The asymmetric catalytic aza-Morita-Baylis-Hillman (aza-MBH) reaction of isatin-derived ketimines with MVK has been established by using chiral amino and phosphino catalysts. The reaction resulted in biomedically important 3-substituted 3-amino-2-oxindole

Full text of DOI:10.1039/c3ob27495k

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Asymmetric catalytic aza-Morita–Baylis–Hillman
reaction for the synthesis of 3-substituted-3-
Cite this: Org. Biomol. Chem., 2013, 11,
1921
aminooxindoles with chiral quaternary carbon centers†
Fang-Le Hu,a Yin Wei,a Min Shi,*a,b Suresh Pindic and Guigen Li*c,d
Received 23rd December 2012,
Accepted 31st January 2013
DOI: 10.1039/c3ob27495k
www.rsc.org/obc
The asymmetric catalytic aza-Morita–Baylis–Hillman (aza-MBH) indoles and pyrroles with N-Boc ketimines in the presence of
reaction of isatin-derived ketimines with MVK has been estab- chiral phosphoric acid catalysts;8 the latter led to the for-
lished by using chiral amino and phosphino catalysts. The reaction mation of 3-aminooxindoles in good yields and with excellent
resulted in biomedically important 3-substituted 3-amino-2-ox- enantioselectivities.9
indoles in good yields (>80% for most cases) and with excellent
In the meanwhile, the Morita–Baylis–Hillman (MBH) reac-
enantioselectivity (90–99% ee). Twenty-eight cases assembled tion has become a powerful and atom-economic tool for con-
with chiral quaternary stereogenic centers have been examined structing enantiomerically enriched α-hydroxycarbonyl or
under convenient systems.
α-aminocarbonyl compounds. In the past one decade, we and
others have extensively studied the Morita–Baylis–Hillman
(MBH) reaction and its aza versions;10,11 among that is the
MBH reaction of N-protected isatin with electron-deficient
alkenes leading to the construction of 3-substituted 3-hydroxy-
oxindoles in good yields and with excellent enantioselectivi-
ties.12 Obviously, the more challenging work is to achieve an
asymmetric catalytic aza-Morita–Baylis–Hillman approach to
chiral 3-aminooxindoles. Herein, we wish to report a highly
enantioselective aza-MBH reaction of isatin-derived N-Boc
ketimines with methyl vinyl ketone (MVK) for the efficient
synthesis of chiral 3-aminooxindoles.
3-Substituted-3-amino-2-oxindoles are core structures in a
variety of natural products and biologically active compounds,1
such as the potent gastrin/CCK-B receptor antagonist
AG-041R,2 the vasopressin VIb receptor antagonist
SSR-14941533 and the antimalarial drug candidate NITD609.4
The development of efficient synthetic protocols leading to
these products, particularly those assembled with quaternary
chiral carbon centers, has been desired and extremely challen-
ging. Recently, significant advances have been achieved in the
development of synthetic methodologies for these targets.
These methods include organocatalytic and metal-catalyzed
asymmetric α-amination,5 chiral auxiliary-controlled diastereo-
selective synthesis of chiral 3-substituted 3-aminooxindoles6
and enantioselective additions of isatin-derived ketimines.7
Very recently, Wang and co-workers reported the asymmetric
addition of 1,3-dicarbonyl compounds onto N-alkoxycarbonyl
ketimines and the asymmetric aza-Friedel–Craft reaction of
Inspired by the fact that chiral amino13,10a and phos-
phino14,15,10c,d derivatives are commonly utilized for asym-
metric MBH and aza-MBH reactions, we came up with chiral
β-isocupreidine (β-ICD) and (R)-2′-diphenylphosphanyl-[1,1′]-
binaphthalenyl-2-ol ((R)-P) as the catalyst candidates for the
reaction of N-Boc ketimine 1a and MVK for our initial investi-
gation. After the catalytic conditions were screened extensively
(for details, see Tables SI-1 and 2 in the ESI†), we found the
best condition is as below: 0.10 mmol of 1a was subjected to
reaction with 0.20 mmol of MVK in the presence of the catalyst
β-ICD (20 mol%) in toluene (2 mL). The reaction occurred to
completion at 0 °C in 72 hours to give product 2a in 96% yield
and 93% ee. We also found that when 20 mol% of (R)-P was
employed as the catalyst, the reaction occurred to completion
in chloroform (2 mL) within a shorter period of 48 h to afford
2a′ in 91% yield and 96% ee (Scheme 1, numbering 2a and 2a′
is for outcomes’ differentiation).
aKey Laboratory for Advanced Materials and Institute of Fine Chemicals, East China
University of Science and Technology, 130 Mei Long Road, Shanghai 200237,
P. R. China
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032,
P. R. China. E-mail: mshi@mail.sioc.ac.cn
cDepartment of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX
79409-1061, USA. E-mail: guigen.li@ttu.edu
dInstitute of Chemistry & BioMedical Sciences, Nanjing University, Nanjing 210093,
P. R. China
†Electronic supplementary information (ESI) available: Experimental pro-
With the optimized condition in hand, we then turned our
attention to the examination of scope and limitations of
this reaction using N-protected ketimines 1 with different
cedures, characterization data of new compounds. CCDC 900656. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ob27495k
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respectively, were also found to be suitable for this reaction,
affording aza-MBH adducts, 2p and 2q, in excellent yields and
enantioselectivity (Table 1, entries 15 and 16). However, when
the t-Bu group of the Boc moiety was replaced by the ethyl
group, the yield and ee value decreased remarkably (Table 1,
entry 18). In order to resolve the steric problem with 4-substi-
tuted substrates in which the t-Bu group of the Boc moiety has
been replaced by the ethyl group, we also synthesized com-
pound 1t and used it in this asymmetric aza-MBH reaction.
However, no desired products were formed under the standard
conditions (Table 1, entry 19). The absolute chemistry of this
Scheme 1 Chiral amine or phosphine-catalyzed asymmetric aza-MBH reaction.
substituents attached to their benzene rings. We found that reaction is represented by the unambiguous determination of
whether electron-withdrawing or donating groups were crystals of product 2e via X-ray diffraction to be “R” configur-
attached to the 5-, 6- or 7-position of the benzene ring of ation (see ESI†).
N-protected ketimines 1, the reaction can smoothly go to com-
Having examined the β-ICD-catalyzed asymmetric aza-MBH
pletion to give product 2 in good to high yields (up to 98%) reaction, we next turned our attention to the chiral phosphine-
and with excellent enantioselectivities (90%–94% ee) (Table 1, catalyzed reaction, the results are summarized in Table 2. As
entries 1–11 and entry 17). As for ketimine 1m with two substi- compared with the β-ICD-catalyzed asymmetric reaction,
tuents on its benzene ring, the corresponding aza-MBH similar results were obtained, affording aza-MBH adducts 2′ in
product 2m was obtained in 97% yield and 90% ee (Table 1, up to 97% yield and 99% ee (Table 2, entries 1–19). The β-ICD
entry 12). Unfortunately, when the electron-withdrawing or catalyst resulted in the same absolute “R” configuration as that
donating substituents were introduced at the 4-position of the of the (R)-P-catalyzed aza-MBH process.
benzene ring, no desired products were formed (Table 1,
Furthermore, we also examined the (S)-BINOL-derived
entries 13 and 14), which is presumably due to the steric catalyst, (S)-P,10d for this reaction. As expected, (S)-P catalyzed
hindrance between the substituents on the 4-position of the the present aza-MBH reaction similarly to (R)-P and resulted in
benzene ring and the N-Boc group. N-Boc ketimines 1p and 1q (S)-2a with the opposite enantioselectivity (95% ee) and in 91%
derived from N-methyl and N-allyl protected isatins, yield (Scheme 2).
Table 1 β-ICD-catalyzed asymmetric aza-MBH reaction
Table 2 (R)-P-catalyzed asymmetric aza-MBH reaction
Entrya
R1
R2
Yieldb (%)
eec (%) Entrya
R1
R2
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1b, 5-CH3
1c, 5-F
1d, 5-Cl
1e, 5-Br
1f, 6-CH3
1g, 6-Cl
1h, 6-Br
1i, 7-F
1j, 7-Cl
1k, 7-Br
1l, 7-CF3
1m, 5-Cl, 7-CH3
1n, 4-CH3
1o, 4,7-Cl2
1p, H
1q, H
1r, 5-CH3O
1s, H
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
Allyl
Bn
Bn
Bn
2b, 86
2c, 97
2d, 98
2e, 97
2f, 93
2g, 98
2h, 98
2i, 97
2j, 98
2k, 92
2l, 84
2m, 97
Trace
Trace
2p, 85
2q, 96
2r, 80
2s, 32
Trace
91
94
93
94
92
94
94
92
92
91
91
90
ndd
ndd
90
90
90
62
ndd
1
2
3
4
5
6
7
8
1b, 5-CH3
1c, 5-F
1d, 5-Cl
1e, 5-Br
1f, 6-CH3
1g, 6-Cl
1h, 6-Br
1i, 7-F
1j, 7-Cl
1k, 7-Br
1l, 7-CF3
1m, 5-Cl, 7-CH3
1n, 4-CH3
1o, 4,7-Cl2
1p, H
1q, H
1r, 5-CH3O
1s, H
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
Allyl
Bn
Bn
Bn
2b′, 93
2c′, 96
2d′, 91
2e′, 97
2f′, 88
2g′, 93
2h′, 93
2i′, 87
2j′, 70
2k′, 78
2l′, 70
2m′, 86
Trace
95
93
99
>99
99
96
97
95
99
99
9
9
10
11
12
13
14
15
16
17
18e
19e
10
11
12
13
14
94
>99
ndd
ndd
95
97
90
Trace
2p′, 85
2q′, 90
2r, 83
2s, 86
Trace
16
17
18e
19e
70
1t, 4,7-Cl2
1t, 4,7-Cl2
ndd
a 1 (0.1 mmol), MVK (0.2 mmol) and catalyst (0.02 mmol) were stirred a 1 (0.1 mmol), MVK (0.2 mmol) and catalyst (0.02 mmol) were stirred
in 2 mL of toluene within 72 h at 0 °C. b Isolated yield. c Determined by in 2 mL of chloroform within 48 h at rt. b Isolated yield. c Determined
chiral HPLC. d Not determined. e The t-Bu group of the Boc moiety in by chiral HPLC. d Not determined. e The t-Bu group of the Boc moiety
1a was replaced by the ethyl group.
in 1a was replaced by the ethyl group.
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Acknowledgements
We thank the Shanghai Municipal Committee of Science and
Technology (11JC1402600), NIH (R21DA031860-01), the Robert
Welch Foundation (D-1361), the National Basic Research
Program of China (973)-2010CB833302, the Fundamental
Research Funds for the Central Universities, and the National
Natural Science Foundation of China for financial support
(21072206, 20472096, 20872162, 20672127, 21121062,
21102166 and 20732008).
Scheme 2 (S)-P-catalyzed asymmetric aza-MBH reaction.
Notes and references
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Scheme 3 Representative aza-MBH product transformation.
For the removal of the N-Boc protection group of 3-amino-2-
oxindoles, 2p′ was used as an example by treating with HCl
(conc.) in ethyl acetate. The cleavage product 3 was obtained
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After treating with acetic anhydride, N-acyl 3-aminooxindole 4
was generated in 70% yield (Scheme 3). The free amino
product 3 would be able to be converted into many other
building blocks in future.
The reaction mechanism for the MBH reaction has been
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reaction of N-sulfonated imines with activated olefins.10 The
key enolate intermediate, which was stabilized by intramole-
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spectroscopy.10d In order to identify the correlation of the ee
values of product 2 with those of catalyst (R)-P during the
present aza-MBH process, a series of control experiments were
performed by employing 1q as the substrate and (R)-P with
different ee values as catalysts under standard conditions (for
details, see Table SI-3 in the ESI†). It was confirmed that there
is no non-linear effect between the ee value of (R)-P and those
of 2q′, indicating that the exclusive reaction transition state
that involves only one molecule of chiral phosphine catalyst
played a role in controlling asymmetric induction during the
present asymmetric aza-MBH reaction.17
The corresponding aza-MBH reaction using N-phosphonyl
and N-phosphinyl imines for GAP (group-assisted purification)
synthesis will be explored in due course.18
In conclusion, the asymmetric aza-MBH reaction of isatin-
derived N-Boc ketimines with MVK in the presence of chiral
amine and phosphine catalysts has been developed for the
first time; this reaction provides an efficient enantioselective
tool for the synthesis of 3-amino-2-oxindoles bearing
quaternary stereogenic centers. The mechanistic study
showed that there is no non-linear effect existing in this asym-
metric catalytic process. Further efforts will be focused on
applications of this reaction for organic and medicinal
synthesis.
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