Asymmetric Morita-Baylis-Hillman reaction of isatins with α,β-unsaturated γ-butyrolactam as the nucleophile

Article abstract of DOI:10.1039/c3ra41115j

α,β-Unsaturated γ-butyrolactam was reported as the nucleophile for the asymmetric Morita-Baylis-Hillman reaction for the first time. This enantioselective MBH reaction, promoted by chiral bisthiourea with isatins as the electrophile, was carried out under

Full text of DOI:10.1039/c3ra41115j

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Asymmetric Morita–Baylis–Hillman reaction of isatins
with a,b-unsaturated c-butyrolactam as the
nucleophile3
Cite this: RSC Advances, 2013, 3, 10127
Received 7th March 2013,
Accepted 7th May 2013
Zhiqiang Duan,a Zirui Zhang,a Ping Qian,a Jianlin Han*ac and Yi Pan*ab
DOI: 10.1039/c3ra41115j
www.rsc.org/advances
a,b-Unsaturated c-butyrolactam was reported as the nucleophile
for the asymmetric Morita–Baylis–Hillman reaction for the first
time. This enantioselective MBH reaction, promoted by chiral
bisthiourea with isatins as the electrophile, was carried out under
mild conditions, resulting in 3-hydroxyl-2-oxindole derivatives in
good to excellent yields and up to 78% ee.
a,b-unsaturated c-butyrolactams has not been reported as
nucleophiles for the MBH reaction until now. c-Butyrolactams
are present in a variety of natural products as well as bioactive
compounds. These frameworks are also very important synthetic
intermediates to many organic compounds.10,11 Herein, we
reported a facile MBH reaction of N-Boc-a,b-unsaturated c-butyr-
olactam 1 with isatin 2 in the presence of DABCO and chiral
bisthiourea, resulting in 3-hydroxy-3-(a,b-unsaturated c-butyrolac-
tam)-2-ones (Scheme 1).
Initially, the reaction of a,b-unsaturated c-butyrolactam 1 with
N-benzyl isatin 2 was carried out in CH2Cl2 with DABCO as the
catalyst at room temperature, yielding 60% of the desired product
3a after 24 h (entry 1, Table 1). Then, the use of a combination of
DABCO and chiral bisthiourea as catalysts was examined in the
reaction, which was believed to synergistically activate the
a,b-unsaturated c-butyrolactam and N-benzyl isatin, subsequently
enhancing the reactivity.12 The reaction proceeded smoothly in
CH2Cl2 to afford 3a with 90% yield and 9% ee when chiral
bisthiourea I (20 mol%) was used (entry 2, Table 1). Next, we
examined the reactions by using chiral bisthiourea catalysts II and
III (entries 3 and 4, Table 1). Higher ee was obtained in the
presence of chiral bisthiourea II (25% ee, entry 3).
The Morita–Baylis–Hillman reaction (MBH reaction), one of the
most useful and popular methods for converting simple starting
materials to densely functionalized products in a catalytic and
atom economic way, has attracted much attention in the past
decades.1 Various activated alkenes, such as enones, acrylonitrile,
enals, acrylates, vinylsulfones and acrylamides have been success-
fully employed in the MBH reaction, and the corresponding
products have been extensively used for various organic reactions
and transformations.2–4
Recently, attention was drawn to 3-hydroxyoxindoles with
substituents at their 3-positions due to their important biological
activities.5,6 Compounds containing this structural motif are also
encountered in a large number of natural and artificial bioactive
compounds.7 Several efficient and facile methods have been
developed for the preparation of 3-substituted oxindoles.8
However, the development of a suitable synthetic method for
the preparation of novel chiral 3-substituted oxindoles is still
highly desirable. Among these reported methods, the MBH
reaction using isatin as the electrophile is a very simple and
straightforward approach for the preparation of biologically
interesting 3-substituted-3-hydroxyl-2-oxindole derivatives.9
Although several active alkenes have been reported as
nucleophiles for the MBH reaction of isatin,9 the use of
The nature of the nucleophilic base is known to have a
pronounced influence on the MBH reaction.13 Therefore, various
bases were screened in combination with chiral bisthiourea II for
the test reaction (entries 5–10, Table 1). When using chiral
bisthiourea II and DMAP or imidazole, 3a was obtained in lower
yield and enantioselectivity (entries 5 and 6, Table 1). A stronger
aSchool of Chemistry and Chemical Engineering, Nanjing University, Nanjing,
210093, China. E-mail: hanjl@nju.edu.cn; Fax: +86-25-83593153;
Tel: +86-25-83593153
bState of Key Laboratory of Coordination, Nanjing University, Nanjing, 210093,
China. E-mail: yipan@nju.edu.cn
cInstitute for Chemistry & BioMedical Sciences, Nanjing University, Nanjing, 210093,
China
Electronic supplementary information (ESI) available: Experimental procedures,
3
full spectroscopic data for new compounds and copies of 1H NMR and 13C NMR
spectra. See DOI: 10.1039/c3ra41115j
Scheme 1 MBH reaction of a,b-unsaturated c-butyrolactam and isatin.
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adduct could be obtained when PPh3 was used as the catalyst,
even though the reaction time was prolonged to 48 h (entry 10,
Table 1).
Table 1 Screening of chiral bisthiourea catalysts and bases for the MBH reaction
of a,b-unsaturated c-butyrolactam 1 with N-benzyl isatin 2aa
To improve the enantioselectivity of the MBH reaction, other
aspects of this reaction, such as the amount of DABCO and chiral
bisthiourea II, reaction temperature and additives were investi-
gated (Table 2). As expected, increasing the chiral bisthiourea II
loading and reducing the DABCO loading improved the enantios-
electivity (entries 1–7, Table 2), and 78% ee was obtained when 100
mol% of chiral bisthiourea II and 5 mol% of DABCO were used
(entry 7, Table 2). Decreasing the temperature affected the reaction
rate, longer reaction time was demanded and no improvement on
the enantioselectivity was found (entry 8, Table 2). Unfortunately,
no desired product 3a was obtained at all when the amount of
DABCO was reduced to 1 mol% (entry 9, Table 2). Addition of 4 Å
MS was effective to decrease the enantioselectivity without loss of
chemical yield (entry 10, Table 2).
For further optimization, the influence of the solvent on the
reaction was investigated (Table 3). As illustrated in Table 3, the
reaction proceeded smoothly in all the examined regular solvents
with good to excellent yields. CH2Cl2 was the most suitable
solvent, and 90% yield and 78% ee were obtained. The reactions
carried out in CHCl3 and THF also gave good enantioselectivities
(72% and 76% ee, entries 2 and 4, Table 3). Obvious lower
enantioselectivities were found when the solvent used was
acetonitrile, 1,4-dioxane, toluene and 1,2-dichloroethane (entries
3, 5, 6 and 7, respectively, Table 3).
Entry
Thiourea
Base
Time (h)
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
—
I
DABCO
DABCO
DABCO
DABCO
DMAP
Imidazole
TMG
DBU
NEt3
PPh3
24
24
24
24
24
24
24
24
24
48
60
90
91
88
79
70
77
81
—
29
25
11
7
II
III
II
II
II
II
II
II
3
20
15
21
—
88
trace
10
a
Reaction conditions: 20 mol% of chiral bisthiourea, 20 mol% of
base, 0.25 mmol N-methyl isatin and 1 equiv. of a,b-unsaturated
c-butyrolactam in 0.5 mL CH2Cl2 at ambient temperature. Isolated
yield after column chromatography. Determined by HPLC analysis
using chiralcel IA column.
b
c
Then, a variety of isatin derivatives with different substituents
on the benzene rings and different protecting groups at the
nitrogen atom were subjected to the reaction to examine the scope
and limitations of this MBH system (Table 4). The N-substituents
of isatins had an obvious effect on the reaction (entries 1–4,
Table 4).
base like DBU afforded the product in a satisfactory yield, but with
lower ee (Table 1, entry 8). Tetramethylguanidine (TMG) and
triethylamine were slightly less efficient than DABCO (entries 7
and 9, Table 1). It was also noteworthy that none of the MBH
The best enantioselectivity was achieved with N-benzyl isatin as
the electrophile (78% ee, entry 1, Table 4). The free isatin could
Table 2 Further optimization of the reaction conditionsa
Entry
II (mol%)
DABCO (mol%)
Additive
T/uC
Time (h)
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
10
30
40
40
40
20
20
30
10
10
10
5
5
1
5
No
No
No
No
No
No
No
No
rt
rt
rt
rt
rt
rt
rt
220
rt
24
24
24
48
48
48
48
120
196
48
90
89
88
91
88
90
85
60
30
33
21
49
53
67
78
76
—
9
60
100
100
100
100
100
No
4 Å MS
trace
88
rt
a
b
The reactions were performed with 0.25 mmol N-methyl isatin and 1 equiv. of a,b-unsaturated c-butyrolactam in 0.5 mL CH2Cl2. Isolated
c
yield after column chromatography. Determined by HPLC analysis using chiralcel IA column.
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Table 3 The survey of solvents for the MBH reactiona
3, Table 4). It appeared that the electronic properties of the
substituent on the phenyl moiety of isatin derivatives had almost
no influence on both yields and enantioselectivities, and compar-
able results were obtained (entries 5–10, Table 4). It is notable that
the substituent position on the phenyl moiety of the N-benzyl
isatin derivatives had obvious influence on the enantioselectivity.
The 6-position substituent for the phenyl ring of N-benzyl isatins
gave higher enantioselectivity than the substituent group on other
positions (entry 11, Table 4).
Entry
Solvent
Time (h)
Yield (%)b
ee (%)c
The determination of the absolute stereochemistry of these
obtained 3-hydroxyl-2-oxindole derivatives was then attempted.
Single crystals suitable for X-ray crystallographic analysis were
obtained. Unfortunately the samples were racemic. The determi-
nation of the absolute stereochemistry will be further studied in
our following work.
1
2
3
4
5
6
7
CH2Cl2
CHCl3
CH3CN
THF
1,4-Dioxane
PhMe
48
48
24
24
24
48
48
90
81
78
89
83
71
77
78
72
53
76
50
33
49
ClCH2CH2Cl
a
The reactions were performed with 100 mol% of chiral bisthiourea
II, 5 mol% of DABCO, 0.25 mmol N-methyl isatin and 1 equiv. of
a,b-unsaturated c-butyrolactam in 0.5 mL solvent at ambient
Conclusions
b
temperature. Isolated yield after column chromatography.
In summary, we have explored the first example of the Morita–
Baylis–Hillman reaction involving the addition of a,b-unsaturated
c-butyrolactam to isatin derivatives catalyzed by chiral bisthiourea
II and DABCO. The corresponding adducts were obtained in good
to excellent yields (75%–91%) and up to 78% ee. Further efforts
are underway with a focus on improving the reaction enantios-
electivity, as well as to elucidate the mechanistic details of this
MBH reaction.
c
Determined by HPLC analysis using chiralcel IA column.
provide the desired product in 91% chemical yields, along with
dramatically lower enantioselectivity (15% ee, entry 2, Table 4).
Employing isatins bearing more sterically bulky substituents such
as triphenylmethyl (entry 4, Table 4) or tert-butylcarbonyl (Boc) on
the nitrogen atom led to the formation of the product in lower
yields and enantioselectivities, and especially for the N-Boc
protecting group, no enantioselectivity was detected at all (entry
Acknowledgements
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (No. 21102071)
and the Fundamental Research Funds for the Central
Universities (No. 1107020522 and No. 1082020502). The
Jiangsu 333 program (for Pan) and Changzhou Jin-Feng-
Huang program (for Han) are also acknowledged.
Table 4 The MBH reaction of isatins with a,b-unsaturated c-butyrolactama
Notes and references
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Entry R1
R2
Product Time (h) Yield (%)b ee (%)c
1
2
H
H
Bn
H
Boc
3a
3b
3c
48
48
72
48
48
48
48
48
48
48
48
48
48
90
91
77
75
85
77
90
75
88
80
91
79
81
78
15
0
3
4
H
H
CPh3 3d
25
45
44
33
24
21
37
77
13
13
5
6
7
8
4-Cl
4-Br
5-Cl
5-Br
5-F
Bn
Bn
Bn
Bn
Bn
3e
3f
3g
3h
3i
3j
3k
9
10
11
12
13
5-Me Bn
6-Cl
7-Cl
7-Br
Bn
Bn
Bn
3l
3m
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a
The reactions were performed with 100 mol% of chiral bisthiourea
II, 5 mol% of DABCO, 0.25 mmol N-methyl isatin and 1 equiv. of
a,b-unsaturated c-butyrolactam in 0.5 mL CH2Cl2 at ambient
b
temperature. Isolated yield after column chromatography.
c
Determined by HPLC analysis using chiralcel IA column and
chiralcel AD-H column.
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