Facile synthesis of functionalized spiro[indoline-3,2'-oxiran]-2-ones by Darzens reaction

Article abstract of DOI:10.3762/bjoc.9.105

A series of functionalized spiro[indoline-3,2'-oxiran]-2-ones was efficiently synthesized by Darzens reaction of phenacyl bromides with isatins both with N-alkyl groups and without N-substituent in the presence of potassium carbonate as a base catalyst. When two equivalents phenacyl bromides were used in the reaction, the N-substitution reaction of isatin also finished with the formation of spiro-oxirane-oxindoles.

Full text of DOI:10.3762/bjoc.9.105

Facile synthesis of functionalized
spiro[indoline-3,2'-oxiran]-2-ones by
Darzens reaction
Qin Fu and Chao-Guo Yan*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 918–924.
College of Chemistry & Chemical Engineering, Yangzhou University,
Yangzhou 225002, China
doi:10.3762/bjoc.9.105
Received: 05 February 2013
Accepted: 09 April 2013
Published: 13 May 2013
Email:
Chao-Guo Yan* - cgyan@yzu.edu.cn
* Corresponding author
Associate Editor: J. P. Wolfe
Keywords:
© 2013 Fu and Yan; licensee Beilstein-Institut.
License and terms: see end of document.
Darzens reaction; isatin; oxindole; oxirane; spiro-epoxyoxindole;
spirooxindole
Abstract
A series of functionalized spiro[indoline-3,2'-oxiran]-2-ones was efficiently synthesized by Darzens reaction of phenacyl bromides
with isatins both with N-alkyl groups and without N-substituent in the presence of potassium carbonate as a base catalyst. When
two equivalents phenacyl bromides were used in the reaction, the N-substitution reaction of isatin also finished with the formation
of spiro-oxirane-oxindoles.
Introduction
The spirooxindole unit is a privileged heterocyclic motif that the diastereoselective and enantioselective synthesis of versa-
forms the core structure of a large family of natural alkaloids tile spiro-oxirane-oxindoles [14-19]. With the aim of expanding
and many pharmacological agents with important bioactivity our previous studies on the synthesis of various spirooxindoles
and interesting structural properties [1-5]. The unique struc- [20-25], we decided to systematically investigate the Darzens
tures and the highly pronounced pharmacological activity reactions of a series of isatins with phenacyl bromides and
displayed by the spirooxindoles have made them attractive syn- report the facile synthesis of versatile spiro[indoline-3,2'-
thetic targets [6-9]. In various heterocyclic and carbocyclic oxiran]-2-ones.
spirooxindoles, the spiro-oxirane-oxindoles are a particular
class of compounds with both spiro-carbon and unstable oxirane Results and Discussion
features in the molecule. These fascinating spiranic frame- In recent years we have found that pyridinium salts react with
works can serve as important building blocks in organic syn- versatile reactive methylene compounds to give different kinds
thesis for the synthesis of large-ring heterocycles [10-13]. As a of products, including functionalized cyclopropanes, 2,3-dihy-
consequence, in recent years much attention has been paid to drofurans, polysubstituted pyridines, pyrido[1,2-a]benzimida-
918

Beilstein J. Org. Chem. 2013, 9, 918–924.
zoles and charge-separated zwitterionic salts [26-31]. We envis- of conditions (Table 1). A careful screening of bases revealed
aged that in situ generated pyridinium ylide might react with the that potassium afforded the product in better yields. The main
reactive carbonyl group of isatins to afford spiro epoxyoxin- problem is that the N-alkylated spiro epoxyoxindole 4 is accom-
doles (Scheme 1). To test this feasibility, the reactions of panied by the formation of spiro epoxyoxindole 3 even if
various substituted isatins with pyridinium salt in the presence equivalent reactants are used, which is consistent with the
of base were examined under different conditions. We were recently reported reactions of isatins with alkylating agents
disappointed that the reactions produced much complicated having an acidic methylene group by Blanco et al. [19]. To our
mixtures and no acceptable results were obtained. Thus, our delight, the spiro epoxyoxindole 3 could be selectively obtained
attention was turned toward the development of straightforward in 85% yield when the reaction was carried out in the system of
reactions of phenacyl bromides with isatins.
K2CO3/CHCl3 at about 50 °C for 10 h. On the other hand the
N-alkylated spiro epoxyoxindole 4 was also successfully
In a preliminary experiment, a model between 5-methylisatin prepared in 90% yield in this system when more than two
(1) and phenacyl bromide (2) was examined under a broad set equivalents of phenacyl bromide were utilized.
Scheme 1: Synthesis of spiro-epoxyoxindole with pyridinium ylide.
Table 1: Reaction of 5-methylisatin (1) with phenacyl bromide (2).
Yield (%)
Entry
Base
Ratios of 1/2
Solvent
Temp. (°C)
Time (h)
3
4
1
NEt3
1:1
EtOH
EtOH
EtOH
EtOH
CHCl3
CHCl3
MeCN
EtOH
toluene
DMF
10–15
10–15
10–15
10–15
10–15
50
24
18
18
18
18
10
10
10
10
10
10
10
10
10
—
40
62
70
78
85
60
56
87
28
66
10
—
—
—
—
—
—
—
—
—
18
—
46
15
77
90
89
2
DABCO
DBU
1:1
3
1:1
4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
1:1
5
1:1
6
1:1
7
1:1
50
8
1:1
50
9
1:1
50
10
11
12
13
14
1:1
50
1:1.2
1:2
CHCl3
CHCl3
CHCl3
DMF
50
50
1:2.2
1:2.2
50
50
919

Beilstein J. Org. Chem. 2013, 9, 918–924.
After obtaining the optimized reaction conditions, various It should be pointed out that some of the spiro epoxyoxindoles
substituted isatins and phenacyl bromides were employed in the 3a–h have been previously prepared by other methods and the
reaction. The results are summarized in Table 2. All reactions related references are also listed in Table 2. The 1H NMR
proceeded very smoothly and eight spiro epoxyoxindoles 3a–h spectra of compounds 3a–h and 4a–e usually show one set of
were obtained in satisfactory yields. Similarly the N-substituted characteristic peaks for each group, especially one singlet at
spiro epoxyoxindoles 4a–e were synthesized in high yields by about 5.10 ppm for one proton of the epoxy unit, which clearly
using an excess of phenacyl bromide. The results are summa- indicates that only one isomer exists in each sample. However,
rized in Table 3. The structures of compounds 3a–h and 4a–e 1H NMR spectra of compounds 3a and 3f clearly displayed that
were characterized by IR, 1H, 13C NMR, and HRMS spectra the trans-isomer existed mainly with ratios of cis/trans isomers
and were further confirmed by single-crystal X-ray diffraction of 1:14 and 1:8, respectively. From Figure 1 and Figure 2 it is
determination of the compound 3c (Figure 1) and 4a (Figure 2). seen that the phenyl group of the oxindole unit and the benzoyl
Table 2: Synthesis of spiro[indoline-3,2'-oxiran]-2-ones 3a–h.
Entry
Compound
R
R’
Yield (%, cis/trans ratio)
Ref.
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
H
H
83 (14:1)
72
[32]
[33]
[32]
—
H
Cl
H
CH3
CH3
F
85
Cl
H
80
78
[34]
[13]
[34]
—
F
Cl
H
77 (8:1)
86
3g
3h
Cl
Cl
Cl
82
Table 3: Synthesis of spiro[indoline-3,2'-oxiran]-2-ones 4a–e.
Entry
Compound
R
R’
Yield (%)
1
2
3
4
5
4a
4b
4c
4d
4e
H
H
93
89
90
85
88
H
Cl
H
CH3
CH3
Cl
Cl
Cl
920

Beilstein J. Org. Chem. 2013, 9, 918–924.
Figure 2: Molecular structure of spiro compound 4a.
Figure 1: Molecular structure of spiro compound 3c.
also established by spectroscopic methods and were confirmed
group existed in the cis-position. This result also indicated that by single-crystal X-ray structure determination of compound 5o
the thermodynamic reaction produces a more stable trans- (Figure 3). 1H NMR spectra showed that a mixture of cis/trans
isomer.
isomers existed in most samples with a large range of different
cis/trans ratios. It is known that the closure of the epoxy ring
To further illustrate the power of this reaction procedure, the would form cis/trans isomers in the Darzens reaction process.
N-substituted isatins were also employed to react with phenacyl Here the N-benzyl and the N-butyl group in the oxindole moiety
bromides under similar reaction conditions. A series of new may decrease the steric effect of formation of the epoxy ring
spiro epoxyoxindoles 5a–p were prepared in high yields and lead to the easier formation of the relatively unstable cis-
(Table 4). The structures of the spiro compounds 5a–p were isomer.
Table 4: Synthesis of spiro[indoline-3,2'-oxiran]-2-ones 5a–p.
Entry
Compound
R
R’
R”
Yield (%, cis/trans ratio)
1
5a
5b
5c
5d
5e
5f
H
CH2Ph
CH2Ph
n-Bu
H
92 [35]
80 (12:1)
88
2
H
Cl
H
3
H
4
H
n-Bu
Cl
H
76 (1:1)
90 (2:1)
86 (3:1)
82 (4:1)
86 (4:1)
80 (5:4)
89 (5:2)
83 (11:1)
92 (3:1)
84 (5:1)
91
5
CH3
CH3
CH3
CH3
F
CH2Ph
CH2Ph
n-Bu
6
Cl
H
7
5g
5h
5i
8
n-Bu
Cl
H
9
CH2Ph
CH2Ph
n-Bu
10
11
12
13
14
15
16
5j
F
Cl
H
5k
5l
F
F
n-Bu
Cl
H
5m
5n
5o
5p
Cl
CH2Ph
CH2Ph
n-Bu
Cl
Cl
H
Cl
81
Cl
n-Bu
Cl
88 (10:1)
921

Beilstein J. Org. Chem. 2013, 9, 918–924.
927, 850, 794 cm−1; 1H NMR (600 MHz, DMSO-d6) δ cis-
isomer: 11.04 (s, 1H, NH), 7.88 (d, J = 7.8 Hz, 2H, ArH), 7.66
(t, J = 7.2 Hz, 1H, ArH), 7.53 (t, J = 7.8 Hz, 2H, ArH), 7.28 (t,
J = 7.2 Hz, 1H, ArH), 6.93 (d, J = 7.8 Hz, 1H, ArH), 6.88 (t, J =
7.2 Hz, 1H, ArH), 6.82 (d, J = 7.8 Hz, 1H, ArH), 5.15 (s, 1H,
CH); trans-isomer: 7.96 (d, J = 7.8 Hz, 2H, ArH), 7.76 (t, J =
7.2 Hz, 1H, ArH), 7.62 (d, J = 7.2 Hz, 1H, ArH), 7.55 (t, J =
7.8 Hz, 2H, ArH), 7.32 (d, J = 7.8 Hz, 1H, ArH), 7.14 (d, J =
7.8 Hz, 1H, ArH), 6.97 (d, J = 7.2 Hz, 1H, ArH), 5.28 (s, 1H,
CH); 13C NMR (150 MHz, DMSO-d6) δ 191.0, 170.8, 144.0,
134.7, 134.4, 131.1, 129.1, 128.0, 123.2, 122.0, 119.3, 110.0,
63.6, 60.4; HRMS–ESI (m/z): [M + Na]+ calcd for
C16H11NNaO3, 288.0631; found, 288.0628.
Typical procedure for the preparation of spiro[indoline-
3,2'-oxiran]-2-ones 4a–e: A mixture of isatin (1.0 mmol),
phenacyl bromide (2.2 mmol) and potassium carbonate
(2.6 mmol) in 20.0 mL of chloroform was stirred at 50 °C for
Figure 3: Molecular structure of spiro compound 5o.
Conclusion
In summary, we have systematically investigated the Darzens 10–24 h (TLC analysis). After cooling, the reaction was
reaction of phenacyl bromides with isatins for the efficient syn- quenched with water. The solvent was evaporated under
thesis of the functionalized spiro epoxyoxindoles. Both the reduced pressure. The residue was recrystallized from ethanol
nonsubstituted isatins and N-alkylated isatins were successfully to give the pure product for analysis.
used in the reactions. The scope and limitation of the reaction
was established. The N-alkylation of the isatins is usually 3'-benzoyl-1-(2-oxo-2-phenylethyl)spiro[indoline-3,2'-
accompanied by the formation of spiro epoxyoxindoles.
oxiran]-2-one (4a): White solid, yield: 93%; mp 188–189 °C;
IR (KBr) ν: 3449, 2929, 1733, 1696, 1613, 1597, 1467, 1351,
1229, 1186, 1101, 930, 786 cm−1; 1H NMR (600 MHz, DMSO-
Experimental
Reagents and apparatus: Melting points were taken on a hot- d6) δ 8.12 (d, J = 7.8 Hz, 2H, ArH), 7.91 (d, J = 7.2 Hz, 2H,
plate microscope apparatus. IR spectra were obtained on a ArH), 7.76 (t, J = 7.2 Hz, 1H, ArH), 7.69 (t, J = 7.2 Hz, 1H,
Bruker Tensor 27 spectrometer (KBr disc). NMR spectra were ArH), 7.63 (t, J = 7.2 Hz, 2H, ArH), 7.55 (t, J = 7.8 Hz, 2H,
recorded with a Bruker AV-600 spectrometer with DMSO-d6 as ArH), 7.31 (t, J = 7.8 Hz, 1H, ArH), 7.14 (d, J = 7.8 Hz, 1H,
solvent and TMS as internal standard (600 and 150 MHz for 1H ArH), 6.96 (t, J = 7.2 Hz, 1H, ArH), 6.90 (d, J = 7.2 Hz, 1H,
and 13C NMR spectra, respectively). HRMS were measured on ArH), 5.56–5.49 (m, 2H, CH2), 5.28 (s, 1H, CH); 13C NMR
a UHR-TOF maXis instrument. X-ray data were collected on a (150 MHz, DMSO-d6) δ 192.5, 190.9, 169.9, 144.9, 134.6,
Bruker Smart APEX-2 diffractometer. Isatins, phenacyl bro- 134.5, 134.2, 134.1, 131.1, 129.1, 128.9, 128.3, 128.0, 122.9,
mide and other reagents are commercial reagents and were used 122.8, 118.7, 110.3, 64.1, 60.2, 47.3; HRMS–ESI (m/z):
as received. Solvents were purified by standard techniques. All [M + K]+ calcd for C24H17KNO4, 422.0789; found, 422.0782.
reactions were monitored by TLC.
Typical procedure for the preparation of spiro[indoline-
Typical procedure for the preparation of spiro[indoline- 3,2'-oxiran]-2-ones 5a–p: A mixture of isatin (1.0 mmol),
3,2'-oxiran]-2-ones 3a–h: A mixture of isatin (1.0 mmol), phenacyl bromide (1.2 mmol) and potassium carbonate
phenacyl bromide (1.0 mmol) and potassium carbonate (1.5 mmol) in 20.0 mL of chloroform was stirred at 50 °C for
(1.2 mmol) in 20.0 mL chloroform was stirred at 50 °C for 10–24 h (TLC analysis). After cooling, the reaction was
10–24 h (TLC analysis). After cooling the reaction was quenched with water. The solvent was evaporated under
quenched with water. The solvent was evaporated under reduced pressure. The residue was recrystallized with ethanol to
reduced pressure. The residue was recrystallized from ethanol give the pure product for analysis.
to give the pure product for analysis.
3'-benzoyl-1-benzylspiro[indoline-3,2'-oxiran]-2-one (5a)
3'-benzoylspiro[indoline-3,2'-oxiran]-2-one (3a) [32]: White [35]: White solid, yield: 92%; mp 154–156 °C; IR (KBr) ν:
solid, yield: 83%; mp 158–159 °C; IR (KBr) ν: 3457, 3180, 3034, 2923, 1730, 1691, 1610, 1463, 1360, 1232, 1185, 1104,
2972, 1735, 1676, 1620, 1597, 1469, 1335, 1219, 1041, 1013, 1007, 923, 870 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.94 (d, J
922

Beilstein J. Org. Chem. 2013, 9, 918–924.
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= 7.8 Hz, 2H, ArH), 7.61 (t, J = 7.2 Hz, 1H, ArH), 7.47 (t, J =
7.8 Hz, 2H, ArH), 7.36–7.30 (m, 5H, ArH), 7.21 (t, J = 7.8 Hz,
1H, ArH), 7.12 (d, J = 7.2 Hz, 1H, ArH), 6.92 (t, J = 7.8 Hz,
1H, ArH), 6.78 (d, J = 7.8 Hz, 1H, ArH), 5.04 (s, 1H, CH), 5.01
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144.6, 135.2, 135.1, 134.5, 131.0, 129.0, 128.9, 128.3, 128.0,
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Single-crystal data for compounds 3c (CCDC 919779), 4a
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Supporting Information File 1
Experimental details and spectroscopic data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-105-S1.pdf]
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This work was financially supported by the National Natural
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