Addition-elimination of nitroalkanes to 3-phenacylideneoxindoles—direct method for the synthesis of 3-alkenylphenacylidene-oxindoles

Article abstract of DOI:10.1080/00397911.2019.1587779

The first addition-elimination of nitroalkanes to 3-phenacylideneoxindoles was developed, affording the corresponding 3-alkenylphenacylidene-oxindoles with high yields.The addition-elimination mechanism of 3-phenacylideneoxindoles with nitroalkanes and re

Full text of DOI:10.1080/00397911.2019.1587779

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Addition-elimination of nitroalkanes to 3-
phenacylideneoxindoles—direct method for the
synthesis of 3-alkenylphenacylidene-oxindoles
Yu-Xuan Fu, Shan-Shan Hu, Shao-Yi Li & Xiao-Juan Li
To cite this article: Yu-Xuan Fu, Shan-Shan Hu, Shao-Yi Li & Xiao-Juan Li (2019):
Addition-elimination of nitroalkanes to 3-phenacylideneoxindoles—direct method for
the synthesis of 3-alkenylphenacylidene-oxindoles, Synthetic Communications, DOI:
10.1080/00397911.2019.1587779
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https://doi.org/10.1080/00397911.2019.1587779
Addition-elimination of nitroalkanes to
3-phenacylideneoxindoles—direct method for the
synthesis of 3-alkenylphenacylidene-oxindoles
Yu-Xuan Fu, Shan-Shan Hu, Shao-Yi Li, and Xiao-Juan Li
School of Chemistry and Chemical Engineering, Xinjiang Normal University, Urumqi, People’s Republic
of China
ABSTRACT
ARTICLE HISTORY
Received 15 December 2018
The first addition-elimination of nitroalkanes to 3-phenacylideneoxin-
doles was developed, affording the corresponding 3-alkenylphenacyli-
dene-oxindoles with high yields.The addition-elimination mechanism
of 3-phenacylideneoxindoles with nitroalkanes and removable NO2
group in concert guarantees the high regioselectivity.
KEYWORDS
Addition-elimination; nitro-
alkanes; 3-
phenacylideneoxindoles
GRAPHICAL ABSTRACT
Introduction
3-phenacylideneoxindoles which can be easily derived from condensation of isatins with
acetophenones,[1–3] have received wide concerns along with developments of isatin
chemistry.[4–7] 3-phenacylideneoxindoles play an important role in rapid construction of
molecule diversity indole derivatives[8–10] such as spiro oxindoles,[11] 3,3-substituted
indoles.[12–16] But the synthesis of 3-alkenylphenacylideneoxindoles might be still in its
beginning stage. Chao-Guo Yan reported the first example of synthesizing 3-alkenylphe-
nacylideneoxindoles by substitution of 3-phenacylideneoxindoles with N-ethoxycarbo-
nylmethylpyridinium bromide,[17,18] later they revealed the preparation of
dispirocyclopentyl-3,3’-bisoxindoles by cyclization of 3-phenacylideneoxindoles with
nitromethane in the presence of DBU.[19] It is well known that nitroalkanes undergo
base-catalyzed 1,4-addition to various a,b-unsaturated carbonyl compounds.[20]
However, if the nitro group is present in a suitable position on the substrate, it could
act as a leaving group and subsequent elimination of nitrous acid from the Michael
CONTACT Xiao-Juan Li
susyss86@163.com
School of Chemistry and Chemical Engineering, Xinjiang Normal
University, Xinyi Road 102, Urumqi 830054, Xinjiang, People’s Republic of China.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

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Y.-X. FU ET AL.
Figure 1. Crystal X-ray diffraction of compound 3a.
adduct.[21–25] Herein, we report 1,4-conjugate addition of 3-phenacylideneoxindoles
with nitroalkanes followed by elimination of nitrous acid, affording 3-alkenylphenacyli-
dene-oxindoles conveniently with 66-98% yields under mild conditions in the presence
of a weak base.
Results and discussion
The reactions of 3-phenacylideneoxindoles with nitromethane in presence of weak bases
were examined, affording 3-alkenylphenacylidene-oxindoles with good yields under
room temperature. The structures of the prepared 3-alkenylphenacylidene-oxindoles
3a–i, 5a–b were characterized with spectroscopic methods (1H and 13C NMR, IR,
HRMS) and confirmed by the X-ray diffraction of single crystal 3a (Figure 1).
Initially, 3-phenacylideneoxindole 1a and nitromethane were selected as the model
substrates (Table 1). Although the reaction proceed slowly in the presence of 1.5 equiv.
of NaHCO3 in methanol (Table 1, entry 1), the expected 3-alkenylphenacylidene-oxin-
doles 3a was isolated in 65% yield. To our delight, after checking the effects of different
bases such as K2CO3, Na2CO3 for this reaction, we found that 1.5 equiv. of K2CO3 were
sufficient to promote this reaction, and the yield of the desired product increased to
83% (Table 1, entry 3). We further explored the reaction in various solvents, and
methanol was demonstrated as the best choice. The reaction was sensitive to tempera-
ture, lower temperature prolonged reaction time (Table 1, entry 6).

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Table1. Optimization of reaction conditions.
Entry
Base
Solvent
Temp (ꢀC)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
9
NaHCO3, 1.5 equiv.
Na2CO3, 1.5 equiv.
K2CO3, 1.5 equiv.
K2CO3, 1.0 equiv.
K2CO3, 2.0 equiv.
K2CO3, 1.5 equiv.
K2CO3, 1.5 equiv.
K2CO3, 1.5 equiv.
K2CO3, 1.5 equiv.
Methanol
Methanol
Methanol
Methanol
Methanol
Methanol
CH2Cl2
Rt
Rt
Rt
Rt
Rt
0
Rt
Rt
Rt
16
8
0.75
2
0.75
16
8
65
79
83
78
71
46
64
72
75
Ethanol
CH3CN
0.75
16
aThe reactions were performed with 1a (0.20 mmol, 1.0 equiv.) and nitromethane (0.20 mmol, 1.0 equiv.) in the pres-
ence of base in 4 mL methanol, under room temperature.
bIsolated yield.
Scheme 1. Possible mechanism for the formation of compound 3a.
The preliminary investigation revealed that an alkane intermediate 2a (separated and
1
characterized by H and 13C NMR, HRMS, IR) formed in 5 min, then converted into
the stable compound 3a completely within 0.5 h (Scheme 1). To our surprise, dispirocy-
clopentyl-3,3’-bisoxindole did not appear in this reaction system. It should be pointed
out that the intermediate 2a, which performed relatively stable in dilute hydrochloric

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Y.-X. FU ET AL.
Table 2. Synthesis of compounds 3a–i.
Entry
Producta
R1
R2
Yieldb (%, Z/E ratioc)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
P-CH3
P-OCH3
p-Cl
p-F
o-CH3
o-F
m-Cl
H
H
H
H
H
H
H
H
H
H
F
83(8:1)
78(7:1)
83(3:1)
83(3:1)
83(4:1)
98(7:1)
66(4:1)
97(4:1)
71(4:1)
Trace
10
3j
OCH3
aReaction condition: 3-phenacylideneoxindoles (0.20 mmol), CH3NO2 (0.20 mmol), K2CO3 (0.30 mmol) in CH3OH (4.0 mL),
room temperature, within 45 min.
c
bYield of pure, isolated product. The Z/E ratio was determined by crude 1H NMR.
acid under room temperature, transformed into product 3a completely in presence of
equal molar K2CO3 within 45 min. When a catalytic amount (30–50%) base was used,
the transformation of 2a to 3a took longer time.
Based on the conjugate addition of nitroalkanes to electron-poor alkenes[21–23]
a
plausible mechanism for the formation of compound 3a–i is proposed, shown as
Scheme 1. Firstly, deprotonation of nitromethane with K2CO3 afforded the desired carb-
anion (A). Secondly, Michael addition of carbanion (A) to the exocyclic double bond of
3-phenacylideneoxindole 1a gives additional intermediate (B). The proton transfer gave
an alkane intermediate 2a, which can be separated and characterized by spectroscopic
methods (1H and 13C NMR, IR, HRMS). The elimination of nitrous acid affording
ꢀ
unsaturated derivative 3a, followed by the double bond isomerization (through proton
migration) gave compound 3a as the final product. The reactions afforded a mixture of
Z/E isomers, while thermodynamically stable Z isomer would be preferentially formed
in this sequential reaction (Table 2, entries 1–8: Z/E isomers > 3:1).
After carefully testing various factors such as base, solvent, temperature, and molar
ratio of substrates and base, we were pleased to find that the best reaction conditions is
the 4 mL methanol solution of 3-phenacylidneoxindole (0.20 mmol) and nitromethane
(0.20 mmol) in the presence of K2CO3 (0.30 mmol) at room temperature. Under the
optimized conditions, the substrate scope was evaluated. All tested 3-phenacyclideneox-
indoles underwent the addition-elimination reaction with nitromethane smoothly,
affording the corresponding 3-alkenylphenacylidene-oxindoles 3a–h with good to excel-
lent yield. The electronic nature and the position of the substituents on oxindole back-
bones or benzoyl groups had little influence on both the yields and the
stereoselectivities (Table 2, entries 1–8: yield > 66%, Z/E isomers > 3:1). Unfortunately,
the substituents on oxindole backbone had a detrimental effect on the reaction (Table 2,
entry 9 and 10). When the substituent on oxindole backbone (R2) is an electron

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Scheme 2. Reactions of 3-phenacylideneoxindoles and 1-nitropropanes.
withdrawing group, the product 3i (Table 2, entry 9) is directly obtained in profitable
yields (71%), whereas, the product 3j (Table 2, entry 10) expressed only trace amounts
when R2 is an electron-donating group. It seemed that the electron-donating group on
oxindole backbone, such as –OCH3, decreased the reactivity of double bond as Michael
acceptors and prevented the addition-elimination reaction.
With methyl substituents on exocyclic C ¼ C double bond, products 3a–i seemed to
1
be the next higher homologs of starting material 3-phenacylideneoxindoles. H NMR
spectra of crude compounds indicated that a mixture of major isomer and minor iso-
mer existed in the most samples. For examples, the Z/E isomers with about 8:1 molecu-
lar ratio existed in crude product 3a (Table 2, entry 1). The structure of representative
compound 3a was further confirmed by single crystal X-ray diffraction. It can be seen
that the carbonyl group of ketone and carbonyl group of oxindole moiety existed in cis-
configuration (Figure 1), which also suggested that the Z isomer of compounds 3a was
1
the major isomer. H NMR spectrum of compound 3a–i indicated that CH3 unit of Z
isomers showed single peaks between 2.45–2.51 ppm, while the CH3 unit of E isomers
1
displayed a singlet between 2.61–2.67 ppm. For example, in the H NMR spectrums of
single Z/E configuration of compound 3c, the CH3 units in Z isomer and E isomer dis-
play one singlet at 2.45 and 2.75 ppm respectively. Purification by flash column chroma-
tography and recrystallization in methanol, single Z isomers of compound 3a–i were
obtained as final products.
In order to further develop the applicability of this reaction, 1-nitropropane was used
to react with 3-phenacylideneoxindoles. To our surprise, compounds 5a–b (separated
1
and characterized by H and 13C NMR, IR, HRMS) were obtained under similar reac-
tion conditionsa in good yields (Scheme 2). The electron withdrawing group on the 3-
1
phenacylideneoxindoles seemed to be necessary for the reaction. In the H NMR spec-
trum of compound 5b, the C ¼ C–H units in E isomer and Z isomer display one triplet
1
at 6.66–6.69 and 5.38–5.42 ppm, respectively. H NMR spectrum of compound 5a indi-
cated that C ¼ C–H unit of E isomers showed triple peaks between 6.65–6.69 ppm, while
1
the C ¼ C–H unit of Z isomers displayed triple peaks between 6.33–6.37 ppm. H NMR
spectra of crude product indicated that E isomer predominately existed in the prepared
samples (E/Z ratio > 5:1). Single E isomer was obtained as final product after purifica-
tion by flash column chromatography and recrystallization in methanol.
Structure of the compounds 5a–b, in which the C ¼ C double bond exists in 3,4-posi-
tions of a,b-unsaturated ketone system,[26] are different with 3a–i. For example, 3-phe-
nacylideneoxindole reacts with 1-nitropropane in the presence of K2CO3 to give
Michael adduct 4a that suffer elimination of nitrous acid affording unsaturated deriva-
tives 5a in good yield.

6
Y.-X. FU ET AL.
Scheme 3. Reactions of 3-phenacylideneoxindoles and 1-nitropropane in the presence of piperazine.
Weak base plays a crucial role in the addition-elimination of 3-phenacylideneoxin-
doles with 1-nitropropane. Notably, the unexpected unsaturated derivatives 6a with exo-
cyclic C ¼ C double bond was obtained in moderate yield (Scheme 3) in the presence of
piperazine. Electron-withdrawing substituent on benzoyl group seemed to be necessary
for the reaction.
Experimental
General procedure for preparing 3-alkenylphenacylidene-oxindoles 2a, 3a–i, 4a,
and 5a–b
K2CO3 (0.30 mmol) was added to a solution of 3-phenacylideneoxindole 1a–i
(0.20 mmol) and nitroalkane (0.20 mmol) in methanol (4 mL) at room temperature.
When the reaction was complete (TLC), 10 mL sat. aq. NH4Cl was added and the mix-
ture was extracted with EtOAc (3 ꢁ 10 mL). The organic layer was combined, washed
with brine, dried (Na2SO4) and concentrated in vacuo. The crude product was purified
by column chromatography (silica gel) and recrystallization in methanol.
(Z)-3-(1-oxo-1-phenylpropan-2-ylidene)indolin-2-one 3a
Yellow solid. m.p: 198-199 ꢀC. IR (KBr): 3137, 3026, 1706, 1469, 1344, 1235, 1104, 961,
1
773, 695 cmꢂ1. H NMR (400 MHz, CDCl3) d: 8.79(s, 1H), 7.94-7.92(d, 2 H, J ¼ 8.0Hz),
7.58-7.54(t, 2 H, J1=8.0Hz, J2=16.0Hz), 7.46-7.43(t, 2 H, J1=8.0Hz, J2=12.0Hz), 7.23-
7.19(t, 1 H, J1=8.0Hz, J2=16.0Hz), 7.06-7.02(t, 1 H, J1=8.0Hz, J2=16.0Hz), 6.65-6.63(d,
1 H, J ¼ 8.0Hz), 2.46(s, 3H). 13C NMR (100 MHz, CDCl3) d: 198.9, 167.8, 147.6, 142.2,
134.7, 133.5, 129.6, 128.8, 128.7, 126.4, 124.0, 122.1, 122.0, 110.6, 18.7. HRMS (ESI)
calcd. for C17H12O2N ([M-H])þ requires m/z 262.0868. Found m/z 262.0866.
(E)-3-(1-oxo-1-phenylpent-2-en-2-yl)indolin-2-one 5a
White solid. m.p: 157-158 ꢀC. IR (KBr): 3191, 3082, 1717, 1651, 1472, 1316, 1218, 975,
751, 646, 579 cmꢂ1 1H NMR (400 MHz, CDCl3) d: 8.15(s, 1H), 7.68-7.66(d, 2 H,
.
J ¼ 8.0Hz), 7.53-7.49(t, 1 H, J1=8.0Hz, J2=16.0Hz), 7.43-7.40(m, 2H), 7.21-7.17(t, 1 H,
J1=8.0Hz, J2=16.0Hz), 7.06-7.04(d, 1 H, J ¼ 8.0Hz), 6.98-6.94(t, 1 H, J1=8.0Hz,
J2=16.0Hz), 6.90-6.88(d, 1 H, J ¼ 8.0Hz), 6.71-6.67(t, 1 H, J1=8.0Hz, J2=16.0Hz),

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SYNTHETIC COMMUNICATIONSV
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4.71(s, 1H), 2.41(s, 2H), 1.15-1.11(t, 3 H, J1=8.0Hz, J2=16.0Hz). 13C NMR (100 MHz,
CDCl3) d: 196.3, 177.9, 152.4, 141.8, 137.8, 136.3, 131.8, 129.5, 128.9, 128.2, 128.1,
123.1, 122.3, 109.8, 46.0, 23.0, 13.4. HRMS (ESI) calcd. for C19H16O2N ([M-H])þ
requires m/z 290.1181. Found m/z 290.1178.
Procedure for the preparation of 6a
To
a
stirred mixture of 3-phenacylideneoxindoles 1g (0.20 mmol) and 1-
nitropropane (0.20 mmol) in methanol (4 mL), a catalytic amount of piperazine
(0.20 mmol) was added. The reaction mixture was stirred at room temperature and
monitored by TLC. After the reaction, the mixture was extracted with EtOAc
(3 ꢁ 5 mL), washed with brine, dried with Mg2SO4 and then concentrated. The crude
product was further purification by column chromatography with 1:5 ethyl acetate and
recrystallization in methanol.
Conclusions
In summary, a special kind of 3-alkenylphenacylidene-oxindoles, in which alkyl exist at
the newly formed C ¼ C double bond positions, were conveniently prepared in 66-98%
yields by addition-elimination of nitromethane with 3-phenacylideneoxindoles in the
presence of a weak base. The reactions have advantages of readily available starting
materials, good yields, and operational simplicity.
Funding
This work was financial supported by National Natural Science Foundation of China
(Grants 21302161).
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