Silica gel-promoted practical synthesis of oxindole-nitrones from diazooxindoles and nitrosoarenes under solvent-free conditions

Article abstract of DOI:10.1039/c5ra21874h

A practical method for the synthesis of oxindole-nitrones promoted by silica gel was developed with good results. The protocol is environmentally friendly as the reaction proceeds under solvent-free conditions with broad substrate scope, and high selectiv

Full text of DOI:10.1039/c5ra21874h

RSC Advances
View Article Online
View Journal | View Issue
COMMUNICATION
Silica gel-promoted practical synthesis of
oxindole–nitrones from diazooxindoles and
nitrosoarenes under solvent-free conditions†
Cite this: RSC Adv., 2015, 5, 105825
a
b
a
Received 20th October 2015
Accepted 1st December 2015
*
Yun-Hao Zhang, Ming-Yue Wu and Wen-Cai Huang
DOI: 10.1039/c5ra21874h
www.rsc.org/advances
A practical method for the synthesis of oxindole–nitrones promoted is still a high demand for the development of an efficient and
by silica gel was developed with good results. The protocol is envi- practical method for the synthesis of ketonitrones with a wide
ronmentally friendly as the reaction proceeds under solvent-free substrate scope under mild and green reaction conditions.
conditions with broad substrate scope, and high selectivity and
Spirooxindoles are privileged structural motifs found in
chemical yield, and the silica gel can be quantitatively recovered and many natural products and unnatural biologically active
reused multiple times.
compounds and the methodologies to construct such inter-
esting structures have attracted the attention of medicinal
chemists and organic chemists.5 For example, highly efficient
and stereocontrolled methods have been developed to build up
biologically active spirooxindole derivatives by Barbas III group
recently.6 We speculated that oxindole–nitrones 3 may play an
important role in this process.7 However, only one synthetic
approach to 3 has been reported via conventional hydroxyl-
amine strategy catalyzed by triuoroacetic acid thus far.7a
Accordingly, efficient preparation of oxindole–nitrones is
essential owing to their wide synthetic utility. More recently, Hu
and Xing group developed a Brønsted acid-catalyzed aromatic
C–H functionalization of electron-rich arenes with diazoox-
indoles via diazonium ion intermediate (Scheme 2).8 Inspired
by their proposed mechanism and based on the highly reactive
property of nitrosoarenes,9 we envisioned that a diazonium ion
generated from diazooxindole would undergo intramolecular
cyclization in the presence of electrophilic nitroso compound to
yield oxaziridine intermediate followed by ring opening to give
Recent years have witnessed a signicant increase in the utili-
zation of nitrones as highly valuable synthetic intermediates for
the construction of complex targets.1 In particular, nitrones can
be employed as versatile 1,3-dipoles for the synthesis of aza-
heterocycles which constitute the backbone of various biologi-
cally active compounds such as isoxazolidines, isoxazolines, b-
amino alcohols and b-lactams.2 Much effort has been devoted to
generate the nitrones from aldehydes, mainly because of their
facile preparation via the condensation of a hydroxylamine with
an aldehyde. In contrast, the preparation of ketonitrones may
not always be accomplished by such a convenient way because
the condensation reactions between ketones and hydroxyl-
amines are highly dependent on the stability of the ketone and
electronic property of the hydroxylamine (type a, Scheme 1).3
And there are certain limitations for the other limited number
of synthetic methodologies (Scheme 1)4 to prepare ketonitrones.
For example, the N-arylation of corresponding oximes inevitably
competes with O-alkylation with metal catalyst (type b),1a while
the reaction of nitroarenes with Grignard reagents is limited in
terms of functional group tolerance (type c).4c The oxidation of
secondary amines is generally very tedious and usually
combines with much excess oxidants (type d).4d–f Overall, there
aDepartment of Pharmaceutical and Bioengineering, School of Chemical Engineering,
Sichuan University, Chengdu 610065, P. R. China. E-mail: hwc@scu.edu.cn
bDepartment of Chemistry, South University of Science and Technology of China,
Shenzhen 518055, P. R. China
† Electronic supplementary information (ESI) available: Experimental procedures
and spectroscopic data of all new compounds. CCDC 1017177 (3u). For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c5ra21874h
Scheme 1 General strategies for the synthesis of ketonitrones.
RSC Adv., 2015, 5, 105825–105828 | 105825
This journal is © The Royal Society of Chemistry 2015

View Article Online
RSC Advances
Communication
Table 1 Optimization of oxindole–nitrone formationa
2a
(equiv.)
Yieldb
(3a) (%)
Entry
Medium
T (ꢀC)
Time (h)
Scheme 2 Strategy for the synthesis of oxindole–nitrones.
1
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
1.0
1.3
1.5
1.5
1.5
1.5
1.5
1.5
1.5
DCM
DCM
DCM
DCM
DCM
DCE
CHCl3
Toluene
26
26
26
40
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
96
36
36
72
36
36
36
36
24
10
5
5
5
5
5
5
5
5
5
94
62
69
92
92
90
93
87
99
71
99
83
92
99
70
64
56
32
92
88
2c
3d
4
rise to oxindole–nitrone (Scheme 2). If this approach is
successful, it would be an excellent method from easily avail-
able starting materials with wide substrate scope under mild
reaction condition. Herein, we report our ndings on the
practical synthesis of oxindole–nitrone from diazooxindole and
nitroso compound (Scheme 1, type e).
5
6
7
8
9
MeOH
H2O
10e
11
12
13
14
15
16
17
18
19
20
Silica gel
Silica gel
Silica gel
Silica gel
Silica gelf
Acidic alumina
Neutral alumina
Basic alumina
AmberliteCG-50
Montmorillonite
Results and discussion
We initiated our studies by mixing N-methyl-3-diazooxindole
with the commercially available nitrosobenzene in dichloro-
methane (DCM) at room temperature (26 ꢀC). To our delight,
the reaction proceeded smoothly and afforded the desired
product in 94% yield as a single E-isomer (Table 1, entry 1),
albeit with a very long reaction time (4 days). To improve the
efficiency, we rstly investigated the reaction using several
Brønsted acids as the catalyst (entries 2 and 3). Indeed, the acids
can signicantly accelerate the reaction. However, the desired
product was only formed in less than 70% yield along with the
formation of hydrolysis product. It should be noted that the
reaction could proceed very well with good result within 36
5
a
Reaction conditions (unless otherwise mentioned): 1a (0.1 mmol), 2a
(0.22 mmol) in dry solvent (1.0 mL) or silica gel (300–400 mesh, 100 mg)
at 60 ꢀC under air. b Determined by 1H NMR spectroscopy using CH2Br2
as an internal standard. c 10 mol% of triuoroacetic acid was used. d 10
e
mol% of p-toluenesulfonic acid was used. About 10% of by-product
was detected based on 1H NMR but it could be partially converted to
f
3a during isolation. Silica gel (300–400 mesh, 1.0 g), triethylamine
(1.0 mL) and DCM (10 mL) were stirred at room temperature for 6 h.
Then, the solid obtained aer ltration was dried at 60 ꢀC for 8 h to
afford the triethylamine-adsorbing silica gel.
ꢀ
hours at 60 C in the absence of any catalyst (entry 5). Further
screening of solvents showed that protic solvent MeOH gave the
best result, while aprotic solvents such as dichloroethane
(DCE), CHCl3 and toluene gave low product yields with a longer
reaction time (entries 6–9). To our surprise, this reaction could (entry 15), which indicates that the mild acidity of silica gel is
be carried out in water with moderate yield and there was a by- necessary to promote this conversion. Apart from silica gel,
product on TLC plate which had a lower Rf value than 3a (entry some other adsorbents have also been tested for this reaction.
10), but when we tried to isolate it by column chromatography When acidic, neutral and basic alumina were used, moderate to
with silica gel, we found it was partially converted to 3a during low yields could be achieved (entries 16–18). Owing to the weak
the isolation. It is well known that silica gel has widely been acidity, Amberlite CG-50 and montmorillonite afforded 3a in
utilized, not only as effective adsorbent for chromatographic comparatively high yields (entries 19 and 20).
separation of organic compounds, but also as a mild acid
catalyst, an accelerator, or a reaction medium which is easily conditions, we expanded the substrate scope of the reaction by
separable from the products aer the reaction.10,11 From an using
variety of substituted diazooxindole with nitro-
Aer identifying the conditions in entry 14 as the optimized
a
environmental and green chemistry point of view, we investi- sobenzene under the optimized conditions. It was found that
gated the silica gel-promoted oxindole–nitrone formation most of the reactions were performed with good yields and
reaction under solvent-free conditions. As expected, the corre- selectivities (Table 2). It appears that the position and the
sponding product was obtained with almost quantitative yield electronic property of the substituents of diazooxindoles have
as a single E-isomer within 5 hours (entry 11). Further screening a very limited effect on the results of this process. For example,
the molar ratio of nitrosobenzene to 1a showed that 1.5 equiv- various aromatic diazooxindoles, bearing electron-donating
alents is enough to make a complete conversion with excellent groups (X ¼ OMe, Me) or electron-withdrawing groups (X ¼ F,
results (entry 14). When triethylamine-adsorbing silica gel was Cl, Br) at the different positions on the aryl ring reacted effi-
applied, the yield decreased signicantly from 99% to 70% ciently with nitrosobenzene to afford the corresponding
105826 | RSC Adv., 2015, 5, 105825–105828
This journal is © The Royal Society of Chemistry 2015

View Article Online
Communication
RSC Advances
Table 2 Substrates scope for diazooxindolesa
Table 3 Substrates scope for nitroso compoundsa
a
Isolated yields. b The reaction was run at 26 ꢀC for 15 hours.
a
Isolated yields. b The reaction was run at 60 ꢀC for 10 h.
Table 4 Reusability of silica gel
products 3a–i in 85–99% yields as a single isomer. Different
protecting groups (Bn, Ac, or Boc) in diazooxindole were also
tolerable to this transformation, providing the desired products
in excellent results (3j–l).
Run
Time (h)
Yield (%)
1
2
3
4
5
6
5
5
5
5
5
5
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
Further exploration of the substrate scope was focused on
the nitrosoarenes (Table 3). Various substituents with different
electronic properties were tolerable, giving the corresponding
products in high yields. The presence of Cl, Br or F at the
indolinone moiety is very important for drug discovery and
halides are very reactive in many transition metal-catalyzed
reactions,12 which offer opportunities for further modica-
tions at these positions. To our profound impression, the
reaction of 3,5-dimethyl- and 3,5-dichloro-nitroso compounds
2o and 2t bearing sterically hindered substituents with different
electronic properties still gave the corresponding products 3o
and 3t with perfect results.
ether to remove the desired product and the excessive nitro-
sobenzene, and then the remained silica gel was dried at 80 ꢀC
under vacuum for 0.5 hour. Table 4 showed the results of the
reaction of diazooxindole 1aꢀ(0.1 mmol) with nitrosobenzene 2a
which was performed at 60 C for 5 hours using the recovered
silica gel. Almost no decrease in the yield was observed aer
running 6 times, the resultant silica gel still completely kept its
original activity.
It is noteworthy that the substrates bearing electron-
withdrawing groups (2p–v) should be carried out at room
ꢀ
temperature (26 C) for better results. The structure of 3u was
determined by X-ray crystallographic analysis (Table 3) and it
was conrmed that it was a single E-isomer.
Conclusions
It is interesting to note that this silica gel-promoted trans-
formation is easy to scale-up. Thus, a gram-scale reaction of 1.0
g of 1a and 0.93 g of 2a was carried out with 3.0 g of silica gel
under solvent-free conditions, furnishing 1.45 g of the desired
product 3a in 99% isolated yield.
To demonstrate the synthetic practicality of this reaction, the
recyclable experiment of the silica gel used in the oxindole–
nitrone formation reaction was examined (Table 4). Aer the
reaction nished, the reaction mixture was washed with diethyl
In summary, we have developed a practical and efficient method
for the synthesis of oxindole–nitrones from easily available
diazooxindoles and nitrosoarenes promoted by silica gel under
solvent-free conditions. With this complementary approach
towards nitrone's synthesis, an array of nitrosoarenes and
diazooxindoles can be tolerated with very wide substrate scope
and good yields as almost a single E-isomer. The protocol is
environmentally friendly as the reaction proceeds under mild
solvent-free conditions in a short period of reaction time with
This journal is © The Royal Society of Chemistry 2015
RSC Adv., 2015, 5, 105825–105828 | 105827

View Article Online
RSC Advances
Communication
high selectivity and chemical yield, and the used silica gel can
be quantitatively recovered and reused several times without
any loss of its activity. Therefore, it may show great potential
application in both laboratory and industry synthesis in the
future. The further application of this useful method and
transformation of resulting oxindole–nitrones are currently
underway in our laboratory and will be reported in due course.
74, 6365; (f) R. W. Murray and M. Singh, J. Org. Chem.,
1990, 55, 2954.
5 (a) C. V. Galliford and K. A. Scheidt, Angew. Chem., Int. Ed.,
2007, 46, 8748; (b) D. Cheng, Y. Ishihara, C. F. Barbas III
and B. Tan, ACS Catal., 2014, 4, 743.
6 (a) B. Tan, N. R. Candeias and C. F. Barbas III, J. Am. Chem.
Soc., 2011, 133, 4672; (b) B. Tan, N. R. Candeias and
C. F. Barbas III, Nat. Chem., 2011, 3, 473; (c) B. Tan,
G. Hernandez-Torres and C. F. Barbas III, J. Am. Chem.
Soc., 2011, 133, 12354; (d) B. Tan, X. Zeng, W. W. Y. Leong,
Z. Shi, C. F. Barbas III and G. Zhong, Chem.–Eur. J., 2012,
18, 63.
7 (a) H.-B. Yang and M. Shi, Org. Biomol. Chem., 2012, 10, 8236;
(b) M. Mehrdad, L. Faraji, K. Jadidi, P. Eslami and H. Sureni,
Monatsh. Chem., 2011, 142, 917; (c) K. Shuji and T. Takashi,
Chem. Lett., 1995, 24, 49.
General procedure for synthesis of oxindole-nitrones on silica
gel
In a round bottom ask diazooxindole derivative 1 (0.1 mmol)
and nitrosoarene 2 (0.15 mmol) were mixed together, and then
silica gel (300–400 mesh, 100 mg) was added at room temper-
ature. The mixture was vigorously stirred at 60 ꢀC for 5 h. Aer
completion of reaction, the slurry was charged for column
chromatography and eluted with petroleum/ethyl acetate (1/4)
to give the product 3 in excellent yield. The structures of the
products were conrmed by their 1H and 13C NMR spectra and
HRMS values.
8 C. Zhai, D. Xing, C. Jing, J. Zhou, C. Wang, D. Wang and
W. Hu, Org. Lett., 2014, 16, 2934.
9 For select examples of the aldol reaction with arylnitroso
compounds, see: (a) G. Zhong, Angew. Chem., Int. Ed., 2003,
42, 4247; (b) C. Palomo, S. Vera, I. Velilla, A. Mielgo and
E. Gomez-Bengoa, Angew. Chem., Int. Ed., 2007, 46, 8054;
(c) M. Lu, D. Zhu, Y. Lu, X. Zeng, B. Tan, Z. Xu and
G. Zhong, J. Am. Chem. Soc., 2009, 131, 4562; (d)
A. Yanagisawa, S. Takeshita, Y. Izumi and K. Yoshida, J.
Am. Chem. Soc., 2010, 132, 5328; (e) K. Shen, X. Liu,
G. Wang, L. Lin and X. Feng, Angew. Chem., Int. Ed., 2011,
50, 4684; (f) C. P. Frazier, D. Sandoval, L. I. Palmer and
J. Read de Alaniz, Chem. Sci., 2013, 4, 3857; For select
examples of the three-component reaction of diazo ester
and nitrosobenzene, see: (g) Z.-J. Xu, D. Zhu, X. Zeng,
F. Wang, B. Tan, Y. Hou, Y. Lv and G. Zhong, Chem.
Commun., 2010, 46, 2504; (h) A. Rajasekar Reddy, Z. Guo,
F.-M. Siu, C.-N. Lok, F. Liu, K.-C. Yeung, C.-Y. Zhou and
C.-M. Che, Org. Biomol. Chem., 2012, 10, 9165; (i)
A. Rajasekar Reddy, C.-Y. Zhou and C.-M. Che, Org. Lett.,
2014, 16, 1048.
Acknowledgements
We thank the School of Chemical Biology & Biotechnology,
Peking University Shenzhen Graduate School for NMR, HRMS,
and X-ray crystallographic structure measurements.
Notes and references
1 (a) D.-L. Mo and L. L. Anderson, Angew. Chem., Int. Ed., 2013,
52, 6722; (b) C. B. Huehls, T. S. Hood and J. Yang, Angew.
Chem., Int. Ed., 2012, 51, 5110; (c) K. V. Gothelf and
K. A. Jørgensen, Chem. Rev., 1998, 98, 863.
2 For selected examples of [3 + 2] cycloaddition involving
nitrone, see: (a) Y. Shi, A. Lin, H. Mao, Z. Mao, W. Li,
H. Hu, C. Zhu and Y. Cheng, Chem.–Eur. J., 2013, 19, 1914;
(b) P. Jiao, D. Nakashima and H. Yamamoto, Angew. Chem.,
Int. Ed., 2008, 47, 2411; (c) D. Nakashima and
H. Yamamoto, J. Am. Chem. Soc., 2006, 128, 9626; (d)
C. Palomo, M. Oiarbide, E. Arceo, J. M. Garcia, R. Lopez
and A. Gonzalez, Angew. Chem., Int. Ed., 2005, 44, 6187; (e)
M. P. Sibi, Z.-H. Ma and C. P. Jasperse, J. Am. Chem. Soc.,
2004, 126, 718.
10 (a) P. Diddams and M. Butters, in Solid Supports and
Catalysts in Organic Synthesis, ed. K. Smith, Ellis Horwood
and PTR Prentice Hall, New York and London, 1992, ch. 1,
3 and 5; (b) R. S. Varma, Green Chem., 1999, 1, 43; (c)
´
C. Coperet, M. Chabanas, R. P. Saint-Arroman and
J. M. Basset, Angew. Chem., Int. Ed., 2003, 42, 156.
11 For selected examples mediated by silica gel, see: (a) Y. Z. Jin,
N. Yasuda and J. Inanaga, Green Chem., 2002, 4, 498; (b)
T. Taniguchi and D. P. Curran, Org. Lett., 2012, 14, 4540;
(c) A. K. Chaturvedi, A. S. Negi and P. Khare, RSC Adv.,
2013, 3, 4500; (d) D. Nietoza, S. Bruna, M. M. Montero-
Campillo, J. Perles, A. M. Gonzalez-Vadillo, J. Mendez,
O. Mo and I. Cuadrado, Chem. Commun., 2013, 49, 9785;
(e) A. Sagar, V. N. Babu and D. S. Sharada, RSC Adv., 2015,
5, 29066.
3 (a) A. Dondoni, S. Franco, F. Junquera, F. L. Merchan,
P. Merino and T. Tejero, Synth. Commun., 1994, 24, 2537;
(b) J. A. Robl and J. R. Hwu, J. Org. Chem., 1985, 50, 5913;
(c) H. G. Aurich and W. Weiss, Tetrahedron, 1976, 32, 159.
4 (a) X. Peng, B. M. K. Tong, H. Hirao and S. Chiba, Angew.
Chem., Int. Ed., 2014, 53, 1959; (b) R. Grigg, J. Markandu,
T. Perrior, S. Surendrakumar and W. J. Warnock,
Tetrahedron, 1992, 48, 6929; (c) G. Bartoli, E. Marcantoni,
M. Petrini and R. Dalpozzo, J. Org. Chem., 1990, 55, 4456;
(d) T. S. Hood, C. B. Huehls and J. Yang, Tetrahedron Lett.,
12 N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457.
´
´
2012, 53, 4679; (e) C. Gella, E. Ferrer, R. Alibes, F. Busque,
P. de March, M. Figueredo and J. Font, J. Org. Chem., 2009,
105828 | RSC Adv., 2015, 5, 105825–105828
This journal is © The Royal Society of Chemistry 2015