Enantioselective Morita-Baylis-Hillman reaction of isatins with acrylates: Facile creation of 3-hydroxy-2-oxindoles

Article abstract of DOI:10.1021/ol102597s

The first tertiary amine catalyzed enantioselective Morita-Baylis-Hillman (MBH) reaction of isatins with acrylates has been demonstrated, allowing asymmetric synthesis of biologically significant 3-substituted-3-hydroxy-2- oxindoles in good yields and wit

Full text of DOI:10.1021/ol102597s

ORGANIC
LETTERS
2011
Vol. 13, No. 1
82-85
Enantioselective Morita-Baylis-Hillman
Reaction of Isatins with Acrylates:
Facile Creation of 3-Hydroxy-2-oxindoles
Fangrui Zhong, Guo-Ying Chen, and Yixin Lu*
Department of Chemistry & Medicinal Chemistry Program, Life Sciences Institute,
National UniVersity of Singapore, 3 Science DriVe 3, Republic of Singapore, 117543
chmlyx@nus.edu.sg
Received October 26, 2010
ABSTRACT
The first tertiary amine catalyzed enantioselective Morita-Baylis-Hillman (MBH) reaction of isatins with acrylates has been demonstrated,
allowing asymmetric synthesis of biologically significant 3-substituted-3-hydroxy-2-oxindoles in good yields and with excellent enantioselectivities.
The C6′-OH group of ꢀ-isocupreidine (ꢀ-ICD) is believed to facilitate the key proton transfer step in the MBH reaction, via an intramolecular
proton relay process.
3-Substituted-3-hydroxy-2-oxindoles are important structural
motifs found in many natural products and therapeutically
useful agents.1 Given their biological significance, and the
fact that different 3-hydroxy stereoisomers induce different
biological activities, asymmetric synthesis of 3-hydroxy-2-
oxindoles has become an intensively investigated research
area. Over the years, many excellent synthetic approaches
based on transition metal catalysis have been developed to
tackle this synthetic challenge. Construction of 3-hydroxy-
oxindoles was realized by metal-mediated arylation2 or
alkylation3 reactions employing isatins as electrophiles.
Shibata and Toru reported catalytic enantioselective hy-
droxylation reactions of both 3-aryl- and 3-alkyl-2-oxindoles
using a DBFOX-Zn(II) complex.4 Parallel to the explosive
growth of organocatalysis, many elegant asymmetric orga-
nocatalytic synthetic methods have been reported in recent
years. One widely used approach is the addition of carbonyl
substrates to isatins via enamine activation, creating chiral
quaternary 3-hydroxy-2-oxindoles.5 Direct hydroxylation of
oxindole substrates represents an alternative strategy. Itoh
et al. achieved asymmetric hydroxylation of oxindoles by
molecular oxygen using a phase-transfer catalyst.6 Very
recently, Barbas and co-workers reported a dimeric quinidine-
(2) (a) Hanhan, N. V.; Sahin, A. H.; Chang, T. W.; Fettinger, J. C.;
Franz, A. K. Angew. Chem., Int. Ed. 2010, 49, 744. (b) Toullec, P. Y.;
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Qin, Y. J. Org. Chem. 2009, 74, 283.
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10.1021/ol102597s  2011 American Chemical Society
Published on Web 12/03/2010

catalyzed enantioselective aminoxygenation of oxindoles to
access 3-hydroxyoxindole derivatives.7
acrolein.14 Herein, we document our independent studies on
a highly enantioselective MBH reaction of isatins with
acrylates. Our process delivers the MBH adducts in high
yields and with excellent enantiomeric purity at ambient
reaction temperature.
We chose the MBH reaction between N-benzyl isatin 5a
and methyl acrylate 6a as a model reaction to start our
investigation, and the catalytic effects of different amine
catalysts 1-4 (Figure 1) were examined. While quinidine
The Morita-Baylis-Hillman (MBH) reaction is one of
the most synthetically valuable reactions for the construction
of densely functionalized products in a highly atom economic
manner.8 The asymmetric version of this reaction has been
extensively studied by employing either chiral amines9 or
phosphines10 as the catalyst. The electrophiles in the MBH
reactions are mostly aldehydes and imines, and the use of
ketones as electrophiles is very limited.11 Owing to their high
electrophilicity, isatin derivatives have emerged as new
electrophilic components for the MBH reaction.12 As part
of our ongoing research program toward enantioselective
creation of quaternary stereogenic centers,13 we were inter-
ested in developing asymmetric MBH reactions employing
isatins as electrophiles, since such processes would yield
tremendously useful 3-substituted-3-hydroxy-2-oxindoles.1
At the outset of our research, the enantioselective MBH
reaction of isatins was unknown. During the preparation of
this manuscript, Zhou and co-workers disclosed an elegant
asymmetric organocatalytic MBH reaction of isatins and
Figure 1. Stuctures of the organocatalysts screened.
(5) (a) Luppi, G.; Cozzi, P. G.; Monari, M.; Kaptein, B.; Broxterman,
Q. B.; Tomasini, C. J. Org. Chem. 2005, 70, 7418. (b) Luppi, G.; Monari,
M.; Correˆa, R. J.; Violante, F. A.; Pinto, A. C.; Kaptein, B.; Broxterman,
Q. B.; Gardenb, S. J.; Tomasini, C. Tetrahedron 2006, 62, 12017. (c) Chen,
J.-R.; Liu, X.-P.; Zhu, X.-Y.; Li, L.; Qiao, Y.-F.; Zhang, J.-M.; Xiao, W.-
J. Tetrahedron 2007, 63, 10437. (d) Malkov, A. V.; Kabeshov, M. A.; Bella,
M.; Kysilka, O.; Malyshev, D. A.; Pluha´eˇkova´, K.; Koeˇovsky´, P. Org. Lett.
2007, 9, 5473. (e) Nakamura, S.; Hara, N.; Nakashima, H.; Kubo, K.;
Shibata, N.; Toru, T. Chem.sEur. J. 2008, 14, 8079. (f) Itoh, T.; Ishikawa,
H.; Hayashi, Y. Org. Lett. 2009, 11, 3854. (g) Angelici, G.; Correˆa, R. J.;
Garden, S. J.; Tomasini, C. Tetrahedron Lett. 2009, 50, 814. (h) Hara, N.;
Nakamura, S.; Shibata, N.; Toru, T. Chem.sEur. J. 2009, 15, 6790. (i)
Xue, F.; Zhang, S.; Liu, L.; Duan, W.; Wang, W. Chem.sAsian J. 2009, 4,
1664.
1, quinidine-based thiourea 2, and biscinchona alkaloid 4
were found to be completely ineffective (Table 1, entries 1,
2, and 4), ꢀ-isocupreidine (ꢀ-ICD) 39a,15 displayed remark-
able catalytic effects, affording the desired adduct in 94%
yield and with 85% ee (entry 3). Different acrylates were
next explored. Employment of ethyl acrylate 6b slighly
improved the enantioselectivity; however, the chemical yield
dropped dramatically (entry 5). tert-Butyl acrylate 6c was
virtually unreactive (entry 6). When hexafluoroisopropyl
acrylate (HFIPA) 6d or 2-naphthyl acrylate 6e was utilized,
the reaction proceeded rapidly, but the enantioselectivity was
disappointing (entries 7-8). Utilization of benzyl acrylate
6f slightly increased the ee of the adduct (entry 9), and 6f
was thus chosen for further studies. A solvent screening16
revealed that CHCl3 was the solvent of choice, delivering
the product in a moderate yield and with 96% ee (entry 10).
Further experimental conditions were investigated in order
to improve the yield of the reaction, without sacrificing the
enantioselectivity. We were pleased to find that the addition
of 4 Å molecular sieves to the reaction mixture was
beneficial. Under the optimized conditions, the MBH product
could be obtained in 83% yield and with 96% ee (entry 13).
The benzyl protection on the nitrogen atom of isatin proved
to be crucial, as the isatin with a free amino group or with
acetyl protection gave very poor results (entries 14-15).
When the reaction was performed in wet CHCl3, a decrease
in enantioselectivity was observed (entry 16).
(6) Sano, D.; Nagata, K.; Itoh, T. Org. Lett. 2008, 10, 1593.
(7) Bui, T.; Candeias, N. R.; Barbas, C. F., III. J. Am. Chem. Soc. 2010,
132, 5574.
(8) For reviews on the MBH reactions, see: (a) Langer, P. Angew. Chem.,
Int. Ed. 2000, 39, 3049. (b) Basavaiah, D.; Rao, A. J.; Satyanarayana, T.
Chem. ReV. 2003, 103, 811. (c) Masson, G.; Housseman, C.; Zhu, J. Angew.
Chem., Int. Ed. 2007, 46, 4614. (d) Basavaiah, D.; Rao, K. V.; Reddy,
R. J. Chem. Soc. ReV. 2007, 36, 1581. (e) Shi, Y.-L.; Shi, M. Eur. J. Org.
Chem. 2007, 2905. (f) Ma, G.-N.; Jiang, J.-J.; Shi, M.; Wei, Y. Chem.
Commun. 2009, 5496. (g) Declerck, V.; Martinez, J.; Lamaty, F. Chem.
ReV. 2009, 109, 1. (h) Basavaiah, D.; Reddy, B. S.; Badsara, S. S. Chem.
ReV. 2010, 110, 5447.
(9) For selected examples, see: (a) Iwabuchi, Y.; Nakatani, M.;
Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219. (b)
Shi, M.; Xu, Y.-M. Angew. Chem., Int. Ed. 2005, 41, 4507. (c) Matsui, K.;
Takizawa, S.; Sasai, H. J. Am. Chem. Soc. 2005, 127, 3680. (d) Raheem,
I. T.; Jacobsen, E. N. AdV. Synth. Catal. 2005, 347, 1701. (e) Abermil, N.;
Masson, G.; Zhu, J. J. Am. Chem. Soc. 2008, 130, 12596.
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Commun. 2003, 1310. (b) Shi, M.; Chen, L.-H.; Li, C.-Q. J. Am. Chem.
Soc. 2005, 127, 3790. (c) Liu, Y.-H.; Chen, L.-H.; Shi, M. AdV. Synth.
Catal. 2006, 348, 973.
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Rudd, M. T. Chem. Commun. 2001, 757. (c) Reddy, M. V. R.; Rudd, M. T.;
Ramachandran, P. V. J. Org. Chem. 2002, 67, 5382.
With the optimized reaction conditions in hand, the
substrate scope was next studied (Table 2). Various N-
alkylated isatins could be used, and excellent enantioselec-
(12) (a) Garden, S. J.; Skakle, J. M. S. Tetrahedron Lett. 2002, 43, 1969.
(b) Chung, Y. M.; Im, Y. J.; Kim, J. N. Bull. Korean Chem. Soc. 2002, 23,
1651.
(13) For our recent examples of creating quaternary chiral centers, see:
(a) Zhu, Q.; Lu, Y. Angew. Chem., Int. Ed. 2010, 49, 7753. (b) Han, X.;
Kwiatkowski, J.; Xue, F.; Huang, K.-W.; Lu, Y. Angew. Chem., Int. Ed.
2009, 48, 7604. (c) Zhu, Q.; Lu, Y. Chem. Commun. 2010, 46, 2235. (d)
Han, X.; Luo, J.; Liu, C.; Lu, Y. Chem. Commun. 2009, 2044. (e) Luo, J.;
Xu, L.-W.; Hay, R. A. S.; Lu, Y. Org. Lett. 2009, 11, 437. (f) Jiang, Z.;
Lu, Y. Tetrahedron Lett. 2010, 51, 1884. (g) Han, X.; Zhong, F.; Lu, Y.
AdV. Synth. Catal. 2010, 352, 2778.
(14) Liu, Y.-L.; Wang, B.-L.; Cao, J.-J.; Chen, L.; Zhang, Y.-X.; Wang,
C.; Zhou, J. J. Am. Chem. Soc. 2010, 132, 15176. A single example
employing ethyl acrylate was reported; however, the yield was 50% and
the reaction was run at -20°C for 4 d.
(15) For a review on cupreines and cupreidines, see: Marcelli, T.; van
Maarseveen, J. H.; Hiemstra, H. Angew. Chem., Int. Ed. 2006, 45, 7496
.
(16) See Supporting Information for the details.
Org. Lett., Vol. 13, No. 1, 2011
83

Table 1. Exploration of the MBH Reaction of Isatins with
Table 2. Enantioselective MBH Reaction of Different Isatins
with Acrylate 6fa
Acrylatesa
entry
R1/R2 (product)
yield (%)b
ee (%)c
1d
2d
3d
4e
5
H/Bn (7a)
83
62
63
88
61
95
67
96
96
95
95
92
94
66
88
76
96
95
93
92
90
92
95
96
92
92
91
94
85
92
91
95
entry cat.
5/6
solvent time (h) yield (%)b ee (%)c
H/p-OMe-Bn (7b)
H/CHPh2 (7c)
H/CPh3 (7d)
H/Ph (7e)
H/p-OMe-Ph (7f)
H/Me (7g)
7-Cl/Bn (7h)
7-F/Bn (7i)
5-F/Bn (7j)
5-Cl/Bn (7k)
5-Br/Bn (7l)
5-NO2/Bn (7m)
5-Me/Bn (7n)
5-OMe/Bn (7o)
5,7-Me/Bn (7p)
1
2
3
4
5
6
7
8
1
2
3
4
3
3
3
3
3
3
3
3
3
3
3
3
5a/6a
5a/6a
5a/6a
5a/6a
5a/6b
5a/6c
5a/6d
5a/6e
5a/6f
5a/6f
5a/6f
5a/6f
5a/6f
5b/6f
5c/6f
5a/6f
THF
THF
THF
THF
THF
THF
THF
48
48
40
48
40
48
1
-
-
94
-
-
-
85
-
88
-
26
71
90
96
94
94
96
33
30
88
6
7d
8
77
<20
93
92
89
53
69
81
83
26
17
85
9
10
11
12
13
14
15e
16e
THF
THF
24
48
48
48
72
72
48
48
48
9
10
11d
12d
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
13d e
,
14d e
,
15d e
,
a Reactions were performed with 5 (0.05 mmol), 6f (0.1 mmol), 3 (0.005
mmol), and 4 Å molecular sieve (20 mg) in anhydrous CHCl3 (100 µL)
under argon. b Isolated yield. c The ee values were determined by HPLC
analysis on a chiral stationary phase. d Reaction was run for 72 h. e The
catalyst loading was 20 mol %.
16f
a Reactions were performed with 5 (0.05 mmol), 6 (0.1 mmol), and the
catalyst (0.005 mmol) in anhydrous solvent (250 µL) under argon. b Isolated
yield. c The ee values were determined by HPLC analysis on a chiral
stationary phase. d Reaction was performed in CHCl3 (100 µL). e Molecular
sieve (4 Å, 20 mg) was added. f Wet CHCl3 (100 µL) was used as the
solvent.
Table 3. Investigation of the Effects of Various Additivesa
tivities were obtained in all the examples examined (entries
1-7), although a slight increase in catalyst loading or longer
reaction time may be required in some cases. The reaction
was applicable to isatins with different aromatic moieties.
Halogenated isatins at the C5 and C7 positions displayed
high reactivity, and the desired adducts were obtained in
nearly quantitative yields and with very high enantioselec-
tivities (entries 8-12). Isatins with electron-rich aryl rings
were found to be less reactive; an increased catalyst loading
could effectively improve the chemical yields of the reactions
(entries 14-16). The presence of the nitro group on the isatin
slightly reduced the enantioselectivity of the MBH adduct,
which may be correlated to the hydrogen bonding capability
of the nitro group (entry 13). The absolute configurations of
the MBH products were determined based on the X-ray
crystal structure of 7h (see the Supporting Information for
details).
entry
cat.
additive
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
3
8
8
8
8
3
3
3
3
-
-
69
<10
<10
11
35
65
62
64
15
96
71
70
32
10
96
88
35
3
100 mol % i-PrOH
10 mol % PhOH
10 mol % PhCOOH
100 mol % i-PrOH
10 mol % PhOH
10 mol % PhCOOH
100 mol % PhCOOH
a A mixture of 5a (0.05 mmol), 6f (0.1 mmol), the catalyst (0.005 mmol),
4 Å molecular sieve (20 mg), and the additive in CHCl3 (100 µL) was
stirred at room temperature. b isolated yield. c Determined by HPLC analysis
on a chiral stationary phase.
Despite intensive research over the years, the mechanism
of the MBH reactions is not entirely clear. Recent elegant
mechanistic studies supported that the intramolecular proton
transfer from the R-carbon atom to the anion at the adjacent
carbon is the rate-determining step (RDS) for the MBH
reaction.17 To gain insights into our reaction mechanism, a
few further experiments were performed and the results are
summarized in Table 3. We were interested in the potential
roles that the C6′-OH of ꢀ-ICD might have played in the
enantioselective MBH reaction. Thus, ꢀ-isocinchonine 8
without the free phenolic hydroxy group was prepared and
applied in the reaction. The desired MBH adduct was
obtained in very low yield, but with 71% ee (entry 2). This
result indicated that the monofunctional cinchona alkaloid
could provide a certain degree of stereochemical control;
however, the C6′-OH group is indispensable in inducing
84
Org. Lett., Vol. 13, No. 1, 2011

excellent enantioselectivity. The influence of adding various
external proton donors was next investigated. With 8
employed as the catalyst, adding i-PrOH (100 mol %) had
little influence on the enantioselectivity (entry 3). On the
other hand, the addition of more acidic phenol (10 mol %)
or benzoic acid (10 mol %) increased the reaction rate and
led to very poor enantioselectivity (entries 4-5). For the
MBH reaction catalyzed by 3, the addition of a large excess
of i-PrOH had little effect; both yield and ee were maintained
(entry 6). The presence of molar equivalence of phenol,
which mimics the phenolic OH group in ꢀ-ICD, led to a
small decrease in both chemical yield and enantioselectivity
(entry 7). With the addition of a stronger proton donor,
benzoic acid at 10 mol %, the enantioselectivity of the
reaction dropped dramatically (entry 8). Moreover, a large
excess of benzoic acid deterred the reaction, yielding virtually
racemic products in extremely poor yield, which may due
to the overstabilization or protonation of the enolate inter-
mediate induced by the benzoic acid (entry 9).
On the basis of the above experimental findings, we
propose the mechanism of ꢀ-ICD-promoted MBH reaction
as shown in Figure 2. The enolate A is generated upon
nucleophilic addition of ꢀ-ICD 3 to the acrylate, which is
stabilized by the C6′-OH group of 3 via an intramolecular
hydrogen bonding interaction. The subsequent aldol reaction
of A with isatin 5a leads to the formation of zwitterionic
intermediate B. The following proton transfer is the key step,
which has been suggested by the recent studies to be the
RDS for the MBH reaction. We believe the acidic proton of
the C6′-OH group serves as a “proton shuttle” to facilitate
the intramolecular proton transfer from the R-carbon to the
neighboring oxygen anion. This proton transfer step also
likely differentiates the four diastereomers of B (pathway
generating the major steroisomer shown), leading to the
creation of the desired isomer C. Finally, intermediate C
undergoes ꢀ-elimination to afford the MBH adduct 7a and
regenerates 3 at the same time. Our study on the additive
effects agrees well with this proposal. Being less acidic than
the phenolic OH, even excess i-PrOH could not interrupt
the intramolecular proton relay process (Table 3, entry 6).
More acidic phenol could assist the proton transfer process
in a nonstereoselective manner, resulting in a decreased ee
(entry 7). When more acidic benzoic acid was introduced, it
competed favorably as the external hydrogen bond donor
with the C6′-OH group in the proton transfer process,
leading to a dramatically decreased enantioselectivity (entry
8). Therefore, it is clear that C6′-OH of 3 plays a critical
Figure 2. Plausible mechanism.
role in the proton transfer process and contributes signifi-
cantly to the overall rate of the reaction and the observed
enantioselectivity.
In summary, we have successfully demonstrated the first
asymmetric MBH reaction of isatins with acrylates. The
reactions proceeded efficiently at room temperature, yielding
the desired adducts in high yields and with excellent
enantioselectivities. The method reported represents a novel
approach to access structurally challenging and biologically
important chiral 3-hydroxy-2-oxindoles. Additive studies
performed suggested that the C6′-OH group of ꢀ-ICD
facilitates the proton transfer step via its participation in an
intramolecular proton relay process. We anticipate the
methodology described here will find wide applications in
the synthesis of novel 3-hydroxy-2-oxindoles and mechanistic
insights gained in this study may facilitate the rational design
of novel catalytic systems for the asymmetric MBH reactions.
Acknowledgment. We thank the National University of
Singapore and the Ministry of Education (MOE) of Sin-
gapore (R-143-000-362-112) for the generous financial
support.
(17) (a) Aggarwal, V. K.; Fulford, S. Y.; Lloyd-Jones, G. C. Angew.
Chem., Int. Ed. 2005, 44, 1706. (b) Price, K. E.; Broadwater, S. J.; Jung,
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S. J.; Walker, B. J.; McQuade, D. T. J. Org. Chem. 2005, 70, 3980. (d)
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Chem. 2009, 74, 3031. (g) Amarante, G. W.; Benassi, M.; Milagre, H. M. S.;
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Supporting Information Available: Representative ex-
perimental procedures, HPLC chromatogram, X-ray structure
and cif file of 7h, and NMR spectra of the products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL102597S
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