IBX-promoted domino reaction of α-hydroxy amides: A facile one-pot synthesis of isatins

Article abstract of DOI:10.1039/c5ra25036f

A novel and temperature-controlled oxidation of α-hydroxy amides in the presence of IBX is described. The divergent one-pot synthesis of isatins and α-formyl amides was achieved in good to excellent yields under metal-free conditions. And these two mild methods can tolerate a variety of functional groups, and are operationally simple.

Full text of DOI:10.1039/c5ra25036f

RSC Advances
View Article Online
View Journal | View Issue
COMMUNICATION
IBX-promoted domino reaction of a-hydroxy
amides: a facile one-pot synthesis of isatins†
Cite this: RSC Adv., 2016, 6, 2870
*
*
Yaoling Wang, Xu Cheng, Zhen Zhan, Xiaojun Ma, Ruifang Nie, Li Hai and Yong Wu
Received 25th November 2015
Accepted 18th December 2015
DOI: 10.1039/c5ra25036f
www.rsc.org/advances
A novel and temperature-controlled oxidation of a-hydroxy amides in reported the synthesis of isatins through direct oxidation of
the presence of IBX is described. The divergent one-pot synthesis of indoles with IBX-SO3K/NaI.17 However, all these reported
isatins and a-formyl amides was achieved in good to excellent yields methods suffer from one or more drawbacks, like the use of
under metal-free conditions. And these two mild methods can tolerate expensive or toxic catalyst, longer reaction time, tedious
a variety of functional groups, and are operationally simple.
synthetic procedures, and low yield of product. Therefore, the
development of effective and direct strategies for the prepara-
tion of isatins, particularly involving a metal-free reaction,
would be highly desirable.
Isatins(indoline-2,3-diones) are one of the most important and
widely occurring structural units in many natural products and
drug intermediates.1 They are also known to act as PET imaging
agents,2 antipsychotic drugs,3 anticancer drugs4 and antiepi-
leptic drugs (Fig. 1).5 Moreover, isatins are versatile building
blocks for the construction of many signicant heterocycles and
spiro-fused frameworks which occur in many natural products
and bioactive molecules such as spirotryprostatins, horsline,
gelsemine, gelseverine, rhynchophylline, and elacomine.6
Consequently, much attention has been paid to their prepara-
tion and many methods are available. Traditionally, there are
two practical approaches to their synthesis: one involves strong
acid- (oen H2SO4) or base-mediated condensation of aniline
On the other hand, hypervalent iodine reagents are exten-
sively used for various transformations in organic synthesis. For
example, iodoxybenzoic acid (IBX) is widely used in oxidation
reactions because of its high efficiency, easy availability, mild
reaction conditions and its stability to moisture and air.18
During the past decades, the use of IBX as the oxidant has been
dramatically increased. Nicolaou et al. have reported a series of
IBX-based synthetic technology: (1) the oxidation of benzylic
sites,19 (2) the cyclization of functionalized anilides to their
heterocyclic counterparts20 and (3) dehydrogenating ketones,
aldehydes and silyl enol ethers to their corresponding
a,b-unsaturated carbonyl compounds.21 And recently, several
IBX or IBX analogues based methodology in water/organic
solvent biphasic system has been established.22
with diethyl ketomalonate (Martinet procedure),7 oxalyl chlo-
8
´
ride (Stolle procedure), or chloral hydrate (Sandmeyer proce-
dure),9 and the other involves introduction of substituents onto
a preexisting aromatic ring.10 Later, several improved protocols
for the construction of isatins have been reported such as aryne-
based methods,11 Sandmeyer modications,12 metal catalyzed
oxidations,13 sulfur ylide mediated carbonyl homologation,14
and C–H amination.15 Recently, Ilangovan and co-workers re-
ported a molecular iodine-promoted synthesis of isatins from
easily accessible 20-aminophenylacetylenes, 20-aminostyrenes,
and 20-amino-b-ketoesters.16 Just later, Bredenkamp et al.
From last year, we have been focusing on the application of
a-formyl amides23 which can be easily synthesized from
Key Laboratory of Drug Targeting and Drug Delivery System of Education Ministry,
Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan
University, Chengdu 610041, P. R. China. E-mail: wyong@scu.edu.cn
† Electronic supplementary information (ESI) available: General reaction
procedure for the synthesis of isatins
2 and a-formyl amides 3 and the
spectroscopic characterization data of new compounds. See DOI:
10.1039/c5ra25036f
Fig. 1 Biologically active molecules containing an isatin moiety.
2870 | RSC Adv., 2016, 6, 2870–2874
This journal is © The Royal Society of Chemistry 2016

View Article Online
Communication
RSC Advances
At the beginning of our investigation, experiments were
carried out using 2-hydroxy-N-methyl-N-phenylacetamide (1a)
as a model substrate. Aer extensive screenings, we were
pleased to nd that IBX was the optimized oxidant for the
synthesis of isatin (Table 1, entries 1–7). Notably, the isatin 2a
was exclusively obtained under this condition (Table 1, entry 1).
For the optimization of the amount of IBX used in the model
reaction, one equivalent was found to be adequate, as neither
larger nor smaller amount showed better yields (Table 1, entries
8–9). Among various solvents examined, DMSO turned out to be
the best choice, while others such as DMF, dioxane and toluene
were less effective (Table 1, entries 10–12). It might be because
IBX only dissolves in DMSO. Further investigation indicated
that temperature was important for this transformation. An
excellent yield has been obtained when the reaction was carried
out at 100 ꢀC (Tabꢀle 1, entry 1). However, with the temperature
increasing to 120 C, the yield of 2a dropped to 87% (Table 1,
entry 13). And no isatin was obtained when the reaction was
conducted below 90 ꢀC (Table 1, entries 15–17). To our surprise,
Scheme 1 Preparation of isatins.
a-hydroxy amides via Swern oxidation. Although Li et al.
developed a copper-catalyzed intramolecular C–H oxidation/
acylation protocol for the synthesis of isatins from a-formyl
amides (Scheme 1a),24 the synthetic method for isatins using
a-hydroxy amides as starting materials hasn't been reported
before. Besides, a-hydroxy amides are important substances in
organic synthesis and valuable agents in medicinal chemistry.25
Therefore, we were very interested in realizing an efficient and
metal-free method for the preparation of isatins from a-hydroxy
amides. During the course of our investigation, unexpectedly,
we found that the reaction conditions were critical for the
products formed (Scheme 1b). When IBX was used as oxidant
and the reaction was conducted in DMSO at 100 ꢀC, the ex-
pected isatins were obtained in good to excellent yields. None-
theless, when reaction temperature dropped to 25 ꢀC, a-formyl
amides were produced as the only products. Here we wish to
disclose the results of the investigation.
ꢀ
when 1a reacted with IBX at 25 C, the oxidant product 3a was
exclusively obtained in 93% yield (Table 1, entry 16). Therefore,
as observed in this study, the optimized conditions for the
synthesis of isatins tend to be: a-hꢀydroxy amides (1.0 mmol) and
IBX (1.0 mmol) in DMSO at 100 C. And the optimized condi-
tions for the synthesis of a-formyl amides tend to be: a-hydroxy
ꢀ
amides (1.0 mmol) and IBX (1.0 mmol) in DMSO at 25 C.
To further dene the scope of this new method for the
synthesis of isatins, a wide range of a-hydroxy amides were
reacted under the optimized conditions. And the results were
summarized in Fig. 2. A host of a-hydroxy amides bearing either
the electron-donating groups such as methyl, methoxy, or
electron-withdrawing groups such as nitro, halogen, were well
Table 1 Optimization of reaction conditionsa
Yieldb (%)
Entry
Oxidant
Solvent
Temp. (ꢀC)
3a
3b
1
2
3
4
5
6
7
IBX
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Dioxane
Toluene
DMSO
DMSO
DMSO
DMSO
DMSO/EA
DMSO
100
100
100
100
100
100
100
100
100
100
100
100
120
90
91
78
41
27
30
0
0
0
6
0
11
0
0
0
0
50
72
61
0
16
61
93
0
DMP
PhI(CF3COO)2
PhI(OAc)2
SeO2
CrO3
NaClO
IBX
IBX
IBX
IBX
IBX
IBX
IBX
IBX
IBX
IBX
IBX
0
8c
9d
10
11
12
13
14
15
16
17e
18d
63
90
29
17
11
87
71
0
50
25
0
90
0
0
85
16
a
Fig. 2 Transformation of a-hydroxy amides (1) to isatins (2). Reaction
conditions: a-hydroxy amides (1, 1.0 mmol), IBX (1.0 mmol) in DMSO
(2 mL) at 100 ꢀC for 3 h.
Reaction conditions: 1a (1 mmol) and oxidant (1 mmol) in solvent
b
(2 mL) under the corresponding temperature for 3 h. Isolated yield.
c
IBX (0.5 mmol). d IBX (2 mmol). e DMSO/EA (v/v ¼ 1 : 2.5).
This journal is © The Royal Society of Chemistry 2016
RSC Adv., 2016, 6, 2870–2874 | 2871

View Article Online
RSC Advances
Communication
Table 2 Synthesis of a-formyl amides from a-hydroxy amidesa
Entry
R1
R2
3
Yieldb (%)
1
2
3
4
5
H
4-MeO
4-Cl
4-(2-Thienyl)
4-(3-NO2C6H4)
Ethyl
Me
Me
Me
Me
3b
3c
3d
3e
3f
95
90
91
82
89
a
Reaction conditions: a-hydroxy amides (1, 1.0 mmol), IBX (1.0 mmol)
b
in DMSO (2 mL) at 25 ꢀC for 3 h. Isolated yield.
Scheme 3 Control experiments for the reaction mechanism.
synthesized from 3a under the optimized conditions in good
yield (Scheme 3b). These results suggested that a-formyl amide
(3a) should be an important intermediate in the synthesis of
isatin. When 3-hydroxy-1-methylindolin-2-one (4a), the ex-
pected product from 3a via Friedel–Cras reaction, was reacted
under the optimized conditions, 96% yield of 2a was obtained
(Scheme 3c). In contrast, when compound 4a was replaced by
1-methylindolin-2-one (5a), the expected product from the
Friedel–Cras reaction of 1a, no isatin was formed (Scheme 3d).
These showed that compound 4a instead of 5a played the role of
intermediate in this transformation. Furthermore, IBA and air
should be the oxidants of the transformation from 4a to 2a
(Scheme 3e–g).
On the basis of the above results, a possible mechanism was
proposed and depicted in Scheme 4. a-Hydroxy amides (1) was
rst converted into a-formyl amides (3) by way of IBX-promoted
oxidation reaction. Subsequently, the aldehyde group of 3 was
activated by acid to undergo intramolecular Friedel–Cras
cyclization to give alcohol 4. Finally, the desired isatin 2 was
obtained aer 4 was oxidized by IBA and/or air.
Scheme 2 Large-scale divergent synthesis.
tolerated during the course of the reaction providing the desired
compounds 2b–2m in moderate to excellent yields. And the
results showed that electron-donating groups could improve
the reaction yields. Notably, the substrates with meta-methyl or
halogens on N-substituted aromatic ring provided a mixture of
4-substituted and 6-substituted isatins, and 2n–2p were major
products from the transformation, which indicated that steric
hindrance had signicant effect on this reaction. Besides,
synthetically useful biphenyl, thienyl and allyl were tolerated in
this transformation, giving 2d and 2o–2w in good yields.
Furthermore, a variety of functional groups such as ether, nitro,
halogen, cyano and allyl were well-suited for this reaction.
Under the optimal conditions as for 3a, a range of reactions
of various a-hydroxy amides (1) with IBX (1.0 equiv.) were
carried out in DMSO at room temperature, and the results are
summarized in Table 2. All the reactions proceeded smoothly to
afford the corresponding a-formyl amides 3b–f in excellent
yields, indicating that the reaction is not sensitive to electronic
effects (Table 2, entries 1–5). And a variety of functional groups
such as ether, nitro and halogen were well-suited for this reac-
tion. Besides, synthetically useful thienyl and biphenyl were
tolerated in this transformation, giving 3e and 3f in good yields
(Table 2, entries 4–5).
Moreover, considering the general application of these two
transformations, we demonstrated the gram-scale progress, and
an example of large-scale reaction with excellent yield of the
desired product is shown in Scheme 2.
A series of control experiments have also been performed to
explore the mechanism of the synthesis of isatins (Scheme 3).
When 2-hydroxy-N-methyl-N-phenylacetamide (1a) was treated
with IBX in 1,4-dioxane under Ar at 100 ꢀC, the target product 3a
was obtained in 72% yield (Scheme 3a). And isatin 2a could be
Scheme 4 A proposed mechanism accounting for the formation of
isatins.
2872 | RSC Adv., 2016, 6, 2870–2874
This journal is © The Royal Society of Chemistry 2016

View Article Online
Communication
RSC Advances
C. Jing, T. Shi, D. Xing, X. Guo and W. Hu, Green Chem.,
2013, 15, 620.
Conclusions
7 (a) A. Guyot and J. Martinet, C. R. Hebd. Seances Acad. Sci.,
1913, 166, 1625; (b) J. Martinet, C. R. Hebd. Seances Acad.
Sci., 1918, 166, 851; (c) J. Bonnefoy and J. Martinet, C. R.
Hebd. Seances Acad. Sci., 1921, 172, 220.
In summary, an efficient and IBX-promoted divergent synthesis
of isatins and a-formyl amides from a-hydroxy amides under
different temperature conditions has been developed. Isatins
was obtained from a-hydroxy amides in good to excellent yields
at 100 ꢀC, while decrease of temperature to 25 ꢀC leads to
a-formyl amides as the major product. These two methods
feature operational simplicity, good functional group tolerance
and metal-free reaction conditions. And further studies for the
utilization of these products are ongoing in our laboratory.
´
´
8 (a) R. Stolle, J. Prakt. Chem., 1922, 106, 137; (b) R. Stolle, Ber.
Dtsch. Chem. Ges., 1913, 46, 3915.
9 (a) T. Sandmeyer, Helv. Chim. Acta, 1919, 2, 234; (b) W. Prinz,
A. Kayle and P. R. Levy, J. Chem. Res., 1978, 168; (c)
A. C. Pinto, A. A. M. Lapis, B. V. da Silva, R. S. Bastos,
J. Dupont and B. A. D. Neto, Tetrahedron Lett., 2008, 49, 5639.
10 (a) O. L. Erdmann, J. Prakt. Chem., 1840, 19, 321; (b)
A. Laurent, Ann. Chim. Phys., 1840, 3, 393; (c)
O. L. Erdmann, J. Prakt. Chem., 1841, 24, 1; (d) A. Laurent,
J. Prakt. Chem., 1842, 25, 430; (e) H. Gericke, J. Prakt.
Chem., 1865, 96, 177; (f) C. Forrer, Ber. Dtsch. Chem. Ges.,
1884, 17, 976; (g) J. S. Yadav, Synthesis, 2007, 693.
Acknowledgements
We are grateful for nancial support from the National Natural
Science Foundation of China (NSFC) (grant number 81373259 &
81573286).
11 D. C. Rogness and R. C. Larock, J. Org. Chem., 2011, 76, 4980.
12 (a) L. L. Klein and M. D. Tufano, Tetrahedron Lett., 2013, 54,
1008; (b) M. Chouhan, K. R. Senwar, R. Sharma, V. Grover
and V. A. Nair, Green Chem., 2011, 13, 2553.
Notes and references
1 (a) J. F. M. da Silva, S. J. Garden and A. C. Pinto, J. Braz. Chem.
Soc., 2001, 12, 273; (b) W. C. Sumpter, Chem. Rev., 1944, 34, 13 (a) B. X. Tang, R. J. Song, C. Y. Wu, Y. Liu, M. B. Zhou,
393; (c) G. S. Singh and Z. Y. Desta, Chem. Rev., 2012, 112,
6104; (d) A. Millemaggi and R. J. K. Taylor, Eur. J. Org.
Chem., 2010, 4527.
2 (a) A. Challapalli, L. M. Kenny, W. A. Hallett, K. Kozlowski,
G. Tomasi, M. Gudi, A. Al-Nahhas, R. C. Coombes and
W. T. Wei, G. B. Deng, D. L. Yin and J. H. Li, J. Am. Chem.
Soc., 2010, 132, 8900; (b) J. Sun, B. Liu and B. Xu, RSC Adv.,
2013, 3, 5824; (c) T. Liu, H. Yang, Y. Jiang and H. Fu, Adv.
Synth. Catal., 2013, 355, 1169; (d) Y. Liu, H. Chen, X. Hu,
W. Zhou and G. J. Deng, Eur. J. Org. Chem., 2013, 4229.
E. O. Aboagye, J. Nucl. Med., 2013, 54, 1551; (b) 14 C. T. Lollar, K. M. Krenek, K. J. Bruemmer and A. R. Lippert,
Q. D. Nguyen, I. Lavdas, J. Gubbins, G. Smith, R. Fortt, Org. Biomol. Chem., 2014, 12, 406.
L. S. Carroll, M. A. Graham and E. O. Aboagye, Clin. Cancer 15 P. C. Huang, P. Gandeepan and C. H. Cheng, Chem.
Res., 2013, 19, 3914; (c) M. Glaser, J. Goggi, G. Smith, Commun., 2013, 49, 8540.
M. Morrison, S. K. Luthra, E. Robins and E. O. Aboagye, 16 G. Satish, A. Polu, T. Ramar and A. Ilangovan, J. Org. Chem.,
Bioorg. Med. Chem. Lett., 2011, 21, 6945; (d) G. Smith,
2015, 80, 5167.
M. Glaser, M. Perumal, Q. D. Nguyen, B. Shan, E. Arstad 17 A. Bredenkamp, F. Mohrb and S. F. Kirsch, Synthesis, 2015,
and E. O. Aboagye, J. Med. Chem., 2008, 51, 8057.
47, 1937.
3 (a) T. M. Bridges, J. Phillip Kennedy, M. J. Noetzel, 18 (a) C. Hartman and V. Meyer, Chem. Ber., 1893, 26, 1727; (b)
M. L. Breininger, P. R. Gentry, P. Jeffrey Conn and
C. W. Lindsley, Bioorg. Med. Chem. Lett., 2010, 20, 1972; (b)
T. M. Bridges, J. Phillip Kennedy and H. P. Cho, Bioorg.
Med. Chem. Lett., 2010, 20, 558.
P. J. Stang and V. V. Zhdankin, Chem. Rev., 1996, 96, 1123; (c)
T. Kitamura and Y. Fujiwara, s, 1997, 29, 409; (d) V. Satam,
A. Harad, R. Rajule and H. Pati, Tetrahedron, 2010, 66,
7659; (e) A. Duschek and S. F. Kirsch, Angew. Chem., Int.
Ed., 2011, 50, 1524.
4 G. Krishnegowda, A. S. Prakasha Gowda, H. R. Tagaram,
K. F. Carroll, R. B. Irby, A. K. Sharma and S. Amin, Bioorg. 19 (a) K. C. Nicolaou, T. Montagnon, P. S. Baran and
Med. Chem., 2011, 19, 6006.
5 C. R. Prakash and S. Raja, Eur. J. Med. Chem., 2011, 46, 6057.
6 (a) D. Cheng, Y. Ishihara, B. Tan and C. F. Barbas, ACS Catal.,
Y. L. Zhong, J. Am. Chem. Soc., 2002, 124, 2245; (b)
K. C. Nicolaou, P. S. Baran and Y. L. Zhong, J. Am. Chem.
Soc., 2001, 123, 3183.
2014, 4, 743; (b) T. Rajasekaran, G. Karthik, B. Sridha and 20 (a) K. C. Nicolaou, Y. L. Zhong and P. S. Baran, Angew. Chem.,
B. V. Subba Reddy, Org. Lett., 2013, 15, 1512; (c)
A. K. Franz, P. D. Dreyfuss and S. L. Schreiber, J. Am. Chem.
Soc., 2007, 129, 1020; (d) W. Li, X. Liu, X. Hao, Y. Cai,
L. Lin and X. Feng, Angew. Chem., Int. Ed., 2012, 51, 8644;
(e) J. Dugal-Tessier, E. A. O'Bryan, T. B. H. Schroeder,
D. T. Cohen and K. A. Scheidt, Angew. Chem., Int. Ed., 2012,
51, 4963; (f) I. Saidalimu, X. Fang, X.-P. He, J. Liang,
Int. Ed., 2000, 39, 625; (b) K. C. Nicolaou, P. S. Baran,
R. Kranich, Y. L. Zhong, K. Sugita and N. Zou, Angew.
Chem., Int. Ed., 2001, 40, 202; (c) K. C. Nicolaou,
P. S. Baran, Y. L. Zhong and J. A. Vega, Angew. Chem., Int.
Ed., 2000, 39, 2525; (d) K. C. Nicolaou, P. S. Baran,
Y. L. Zhong, S. Barluenga, K. W. Hunt, R. Kranich and
J. A. Vega, J. Am. Chem. Soc., 2002, 124, 2233.
X. Yang and F. Wu, Angew. Chem., Int. Ed., 2013, 52, 5566; 21 (a) K. C. Nicolaou, Y. L. Zhong and P. S. Baran, J. Am. Chem.
(g) A. Bhunia, T. Roy, P. Pachfule, P. R. Rajamohanan and
A. T. Biju, Angew. Chem., Int. Ed., 2013, 52, 10040; (h)
Soc., 2000, 122, 7596; (b) K. C. Nicolaou, T. Montagnon and
P. S. Baran, Angew. Chem., Int. Ed., 2002, 41, 993; (c)
This journal is © The Royal Society of Chemistry 2016
RSC Adv., 2016, 6, 2870–2874 | 2873

View Article Online
RSC Advances
Communication
K. C. Nicolaou, D. L. F. Gray, T. Montagnon and 24 B. X. Tang, R. J. Song, C. Y. Wu, Y. Liu, M. B. Zhou, W. T. Wei,
S. T. Harrison, Angew. Chem., Int. Ed., 2002, 41, 996.
G. B. Deng, D. L. Yin and J. H. Li, J. Am. Chem. Soc., 2010, 132,
22 (a) A. P. Thottumkara, M. S. Bowsher and T. K. Vinod, Org.
8900.
´
Lett., 2005, 7, 2933; (b) A. Schulze and A. Giannis, 25 (a) O. Merino, B. M. Santoyo, L. E. Montiel, H. A. Jimenez-
´
Synthesis, 2006, 257; (c) U. Muhammet, A. Matsujiro and
I. Kazuaki, J. Am. Chem. Soc., 2009, 131, 251.
Vazquez, L. G. Zepeda and J. Tamariz, Tetrahedron Lett.,
2010, 51, 3738; (b) L. Y. Shteinberg, Russ. J. Appl. Chem.,
2009, 82, 613.
23 Z. Zhan, X. Cheng, X. J. Ma, J. Li, L. Hai and Y. Wu,
Tetrahedron, 2015, 71, 6928.
2874 | RSC Adv., 2016, 6, 2870–2874
This journal is © The Royal Society of Chemistry 2016