Investigation of regioselectivity in the synthesis of spiro [pyrrolidine-2,3′-oxindoles] by use of the Huisgen reaction

Article abstract of DOI:10.1007/s11164-012-0770-z

The Huisgen reaction has been used to synthesize five-membered heterocyclic compounds in high yield and with high regio and stereoselectivity. In the synthesis of spiro [pyrrolidine-2,3′-oxindole] derivatives from isatin, α-amino acids, and (E)-β-phenyl nitroolefins, two regioisomers were obtained in each reaction. The regioselectivity of the major product was found to be different from that in reported work, and was investigated at the B3LYP/6-311G*level of theory. On the basis of this new finding, several conditions, for example molar ratio, solvent, and temperature, which affect the regioselectivity of this reaction were investigated; the results obtained are discussed. It was found that the regioselectivity of this reaction was affected by solvent and temperature, irrespective of the ratio of the reactants. Low temperature and high solvent polarity leads to high regioselectivity, and protic solvents result in higher yield and regioselectivity. These results are of benefit for regioselective synthesis of some compounds.

Full text of DOI:10.1007/s11164-012-0770-z

Res Chem Intermed
DOI 10.1007/s11164-012-0770-z
Investigation of regioselectivity in the synthesis of spiro
[pyrrolidine-2,30-oxindoles] by use of the Huisgen
reaction
•
Gang Chen Yan-qing Miao Rui Zhou Li Zhang
•
•
•
•
Jie Zhang Xiao-jiang Hao
Received: 12 July 2012 / Accepted: 16 August 2012
Ó Springer Science+Business Media B.V. 2012
Abstract The Huisgen reaction has been used to synthesize five-membered het-
erocyclic compounds in high yield and with high regio and stereoselectivity. In the
synthesis of spiro [pyrrolidine-2,30-oxindole] derivatives from isatin, a-amino acids,
and (E)-b-phenyl nitroolefins, two regioisomers were obtained in each reaction. The
regioselectivity of the major product was found to be different from that in reported
work, and was investigated at the B3LYP/6-311G* level of theory. On the basis of
this new finding, several conditions, for example molar ratio, solvent, and tem-
perature, which affect the regioselectivity of this reaction were investigated; the
results obtained are discussed. It was found that the regioselectivity of this reaction
was affected by solvent and temperature, irrespective of the ratio of the reactants.
Low temperature and high solvent polarity leads to high regioselectivity, and protic
solvents result in higher yield and regioselectivity. These results are of benefit for
regioselective synthesis of some compounds.
Keywords Huisgen reaction ꢀ Regioselectivity ꢀ Regioisomer ꢀ
Spiro [pyrrolidine-2,30-oxindole]
G. Chen (&) ꢀ R. Zhou ꢀ L. Zhang ꢀ J. Zhang
College of Chemistry and Chemical Engineering, Xi’an Shiyou University, Xi’an 710065
Shaanxi, People’s Republic of China
e-mail: gangchen@xsyu.edu.cn
Y. Miao
Department of Pharmacology, Xi’an Medical University, Xi’an 710068, Shaanxi
People’s Republic of China
X. Hao
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute
of Botany, Chinese Academy of Sciences, Kunming 650201, People’s Republic of China
e-mail: haoxj@mail.kib.ac.cn
123

G. Chen et al.
Introduction
The Huisgen reaction, also known as 1,3-dipolar cycloaddition, has been used to
synthesize many five-membered heterocyclic compounds [1–3]. Among these,
natural product-like spiro-oxindole derivatives have attracted much intention
because of their varied and potent bioactivity [2–6]. Because of their interesting
bioactivity, many spiro-oxindole derivatives have been synthesized in our work
[6–10]. In the Huisgen reaction of isatin, a-amino acids, and (E)-b-aryl nitroolefins,
regioselectivity was different from that in other reported work; this was investigated
by using the B3LYP/6-311G* level of theory [10]. The work is summarized in
Fig. 1. In this paper, we provide more information about the factors affecting the
regioselective synthesis of spiro-oxindole compounds by use of the Huisgen
reaction.
Results and discussion
In our previous work, two regioisomers were obtained (4a and 4b) in Huisgen
reactions of isatin, proline, and (E)-b-phenyl nitroolefins. What was most interesting
was that the major product (4a) had different regioselectivity from that of reported
spiro-oxindole derivatives. In the major product, the nitro group shows correlation
with C-4 of the newly constructed pyrroline and the phenyl groups connected to
C-3. Theoretical study revealed there is an interaction, p–p stacking, between the
azomethine ylide and the (E)-b-phenyl nitroolefin before reaction and the lower
energy barrier between the stacking state and the transition state leads to the single
NO2
O
N
NO2
N
COOH
+
+
3
N
H
N
H
O
NO2
N
O
N
O
H
H
2
1
4b
4a
TS-4b
56.7
TS-4a
50.7
reactant
26.9
reactant
11.4
SS-4b
SS-4a
+
N
-
+
NO2
N
-
Ph
O
N
O
N
H
Ph
H
O2
N
61.3
66.1
N
N
NO2
NO2
N
H
O
N
H
O
regioisomer-4a
regioisomer-4b
Fig. 1 Energy change (kJ/mol) of the Huisgen reaction between isatin, L-proline, and (E)-b-phenyl
nitroolefins
123

Investigation of regioselectivity of the Huisgen reaction
or main product as described in Fig. 1. The stability of the stacking state of different
conjugated systems with the oxindole group was determined from the calculations
as: benzoyl group [ ester group [ phenyl group [ nitro group. This mechanism
was found to be applicable to all Huisgen reactions.
In synthetic practice, more attention should be paid to the conditions, especially
the importance of molar ratio, solvent, and temperature in regioselectivity. So, in
subsequent research, the molar ratio was studied first under typical conditions of
room temperature (30 °C) in the solvent methanol–H2O 3:1 (v/v), and reaction
overnight; the results are shown in Table 1. It is apparent from this table that the
total yield of 4a and 4b increases with increasing amount of (E)-b-phenyl
nitroolefin. When the molar ratio is 1.2, the total yield is 89.7 %, and use of more
(E)-b-phenyl nitroolefin does not improve the yield. The appropriate isatin–proline–
(E)-b-phenyl nitroolefin molar ratio was therefore selected as 1:1:1.2. With different
molar ratios the selectivity for 4a and 4b (i.e. 4a:4b) hardly changed, in other words,
the regioselectivity of this reaction is independent of molar ratio.
In the second step, the effect of reaction temperature on yield and regioselectivity
was studied under the conditions isatin–proline–(E)-b-phenyl nitroolefin molar ratio
1:1:1.2, in the solvent methanol–H2O 3:1 (v/v), and reaction overnight; the results
were summarized in Table 2. Temperatures in the range 30 to 68 °C (b.p. methanol)
were investigated; the results showed the total yield of 4a and 4b decreased as the
temperature was increased. The reason might be increased side reactions in addition
to the Huisgen reaction. It is remarkable that regioselectivity for 4a decreased with
the increasing temperature, because the different between the two energy barriers
between the stacking states and the transition states is easier to overcome at high
temperature. In other words, low temperature leads high yield and regioselectivity
for 4a.
The effect of methanol-to-H2O volume ratio on the yield and regioselectivity was
investigated under the conditions isatin–proline–(E)-b-phenyl nitroolefin molar ratio
Table 1 Effect of molar ratio
on yield and regioselectivity
Isatin–proline–(E)-b-phenyl
nitroolefin molar ratio
Yield
(%) 4a
Yield
(%) 4b
4a:4b
1:1:1.0
1:1:1.1
1:1:1.2
1:1:1.3
53.5
66.7
84.5
85.1
3.2
3.9
5.2
5.2
16.7
17.1
16.3
16.4
Table 2 Effect of temperature
on yield and regioselectivity
Temperature (°C)
Yield (%) 4a
Yield (%) 4b
4a:4b
30
40
50
60
68
84.5
82.6
73.8
71.9
67.6
5.2
6.5
7.5
8.6
8.5
16.3
12.7
9.8
8.4
8.0
123

G. Chen et al.
Table 3 Effect of methanol-to-
H2O volume ratio on yield and
regioselectivity
Methanol-to-H2O volume
ratio
Yield (%)
4a
Yield (%)
4b
4a:4b
100:0
100:1
50:1
10:1
3:1
60.4
58.7
62.8
70.4
84.5
24.6
18.5
15.6
10.4
5.2
2.5
3.2
4.0
6.8
16.3
1:1:1.2, at room temperature, and reaction overnight; the results are summarized in
Table 3. It is apparent from the table that total yield decreases when a small amount
of H2O is added but then increases with increasing amount of H2O. The
regioselectivity, i.e. the ratio of 4a to 4b, changes substantially, from 2.5 to 16.3.
Too much H2O reduces the solubility of the (E)-b-phenyl nitroolefin, however, so
more solvent has to be used.
It is common sense that the a-amino acid initially reacts with the isatin by a
typical addition reaction to form intermediate A. The dipolarophile (intermediate B)
is generated in situ via decarboxylative condensation of isatin with the a-amino
acid, with simultaneous dehydration, yielding the azomethine ylide (intermediate C)
which is a steady resonance hybrid of dipolarophiles (as shown in Scheme 1) [11,
12]. In this process, the decarboxylation and dehydration are the key steps, so the
total yield decreases as a small amount of water is added, because of inhibition of
dehydration. As the amount of water is increased, the polarity of the solvent
increases, which helps to stabilize the dipolarophiles and/or azomethine ylide and
leads to an increase in total yield. It can be found from experiments and theoretical
analysis that high polarity benefits regioselectivity for 4a.
O
O
O
O
H
N
COOH
+
N
O
O
N
H
H
H
N
H
A
- CO2, - H2O
-
+
N
N
-
+
N
O
N
O
C
B
H
H
Scheme 1 Process of formation of the azomethine ylide
123

Investigation of regioselectivity of the Huisgen reaction
Table 4 Effect of solvent on
Solvent
Yield (%) 4a
Yield (%) 4b
4a:4b
yield and regioselectivity
Methanol
Ethanol
50.4
50.2
49.7
44.4
41.8
39.7
32.7
24.6
25.5
17.6
28.1
12.5
18.2
19.8
2.0
2.0
2.8
1.6
3.3
2.2
1.7
i-Propanol
n-Butanol
THF
Pyridine
Acetonitrile
Finally, the effect of the solvent on yield and regioselectivity was investigated
under the conditions isatin–proline–(E)-b-phenyl nitroolefin molar ratio 1:1:1.2, at
room temperature, and reaction overnight; the results are summarized in Table 4.
Seven solvents were tested in this Huisgen reaction. The results show that total
yields in the strong protic solvents methanol, ethanol, i-propanol, and n-butanol, are
over 70 %, i.e higher than in weak protonic solvent, but regioselectivity is lower
than that in THF, in which regioselectivity for 4a was highest.
Conclusions
In conclusion, the regioselectivity of the Huisgen reaction of isatin, proline, and
(E)-b-phenyl nitroolefins was affected by solvent and temperature, and was
independent of the ratio of the reactants. Low temperature leads to high yield and
high regioselectivity for 4a, and high solvent polarity leads to high regioselectivity
for 4a. In addition, strong protic solvents result in higher yield and better
regioselectivity for 4a. We believe these effects of the reaction conditions will be
similar in many regioselective Huisgen reactions.
Experimental section
General remarks
All starting materials and solvents (A.R. grade) are commercially available and
were used without further purification. NMR spectra were recorded, in the solvents
1
indicated below, on a Bruker DPX500 spectrometer, operating at 500 MHz for H
and 125 MHz for 13C; d values are reported in ppm and J values in hertz. Mass
spectra were recorded on a Micromass Platform II spectrometer, using the direct-
inlet system operating in electron-impact (EI) mode.
General procedure for synthesis of spiro [pyrrolidine-2,30-oxindoles]
The required (E)-b-phenyl nitroolefin was prepared by reaction of nitromethane
with benzaldehyde in AcOH–AcONH4 buffer. A solution of isatin (1 mmol),
123

G. Chen et al.
a-amino acid (1 mmol), and (E)-b-phenyl nitroolefin (1.2 mmol) was heated under
reflux in a specific solvent. When the isatin had been completely consumed
(monitored by TLC), the solvent was removed under reduced pressure and the
residue was subjected to column chromatography (silica gel, petroleum ether–ethyl
acetate 4:1) to give the desired products.
1
4a: yield 8.5 %; H NMR (D6-acetone, 500 MHz), d: 9.67 (1H, s), 7.55 (2H, d,
J = 7.5 Hz), 7.48 (1H, d, J = 7.5 Hz), 7.41 (2H, m), 7.31 (2H, m), 7.04 (1H, m),
6.97 (1H, d, J = 7.5 Hz), 5.75 (1H, d, J = 11.5 Hz), 4.41 (1H, m), 3.93 (1H, m),
2.70 (1H, m), 2.56 (1H, m), 1.88–1.99 (4H, m); 13C NMR (D6-acetone, 125 MHz),
d: 178.2, 144.0, 138.3, 131.4, 129.8, 128.6, 128.5, 127.2, 124.0, 122.6, 111.3, 97.4,
73.7, 71.2, 54.0, 48.6, 31.1, 27.6; EI–MS, m/z: 349 (M?), HRMS (ESI–TOF) calcd
for C20H19N3O3Na, 272.1324; found, 272.1322.
4b: yield 73.1 %; 1H NMR (D6-acetone, 500 MHz), d: 7. 87 (1H, d, J = 7.5 Hz),
7.23 (2H, m), 7.14 (3H, m), 7.07 (1H, m), 6.72 (1H, d, J = 7.5 Hz), 6.37 (1H, dd,
J = 10.5, 9.5 Hz), 4.75 (1H, m), 4.57 (1H, d, J = 11.0 Hz), 3.37 (1H, m), 2.74 (1H,
m), 2.02 (1H, m), 1.97 (1H, m), 1.74 (1H, m), 1.44 (1H, m); 13C NMR (D6-acetone,
125 MHz), d: 178.0, 144.0, 134.4, 130.7, 129.4, 129.2, 128.5, 127.6, 126.1, 122.5,
110.6, 92.7, 75.7, 64.3, 52.9, 51.7, 28.6, 26.2; EI–MS, m/z: 349 (M?), HRMS (ESI–
TOF) calcd for C20H19N3O3Na, 272.1324; found, 272.1321.
Acknowledgments This work was financially supported by grants from the Scientific and Technolog-
ical Plan Projects of Shaanxi Province of China (2012KJXX-40) and the Scientific Research Program
Funded by Shaanxi Provincial Education Department (12JK0582, 12JK0589).
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