Catalyst-free one-pot tandem reduction of oxo and ene/yne functionalities by hydrazine: Synthesis of substituted oxindoles from isatins

Article abstract of DOI:10.1002/ejoc.201402038

An unprecedented one-pot tandem reduction of oxo and ene/yne functionalities of substituted isatins is disclosed for the synthesis of oxindole derivatives in excellent yields. The reaction is simply performed by treating N-(2-alkenyl)/propargylisatins wit

Full text of DOI:10.1002/ejoc.201402038

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402038
Catalyst-Free One-Pot Tandem Reduction of Oxo and Ene/Yne Functionalities
by Hydrazine: Synthesis of Substituted Oxindoles from Isatins
Mukund Jha,*[a] Ganesh M. Shelke,[a,b] and Anil Kumar[b]
Keywords: Synthetic methods / Reduction / Nitrogen heterocycles / Fused-ring systems
An unprecedented one-pot tandem reduction of oxo and ene/
yne functionalities of substituted isatins is disclosed for the
(25%) under catalyst-free refluxing conditions. The re-
duction process appears to be quite unique and proceeds
synthesis of oxindole derivatives in excellent yields. The re- quite efficiently without the aid of any catalyst at ambient
action is simply performed by treating N-(2-alkenyl)/prop-
pressure.
argylisatins with an excess amount of hydrazine hydrate
carbon–carbon bonds.[16] It is believed that hydrazine un-
dergoes oxidation to produce diimide (N2H2) in situ, which
acts as a transfer-hydrogenation agent in the reduction pro-
cess.[17] Oxidants such as H2O2, NaIO4, K3[(FeCN)6], and
even molecular oxygen have been shown to catalyze the se-
lective reduction of unsaturated carbon–carbon bonds by
using hydrazine.[17] The oxidation of hydrazine to diimide
by using molecular oxygen typically requires a catalyst (e.g.,
copper, iron, and guanidine salts and various flavin deriva-
tives) to promote the reaction.[17] Catalyst-free oxidation of
hydrazine with molecular oxygen is rather inefficient, as it
requires an excess amount of hydrazine and proceeds at a
sluggish rate.[16] The reactive diimide intermediate is also
prone to disproportionation (reformation to hydrazine) and
over oxidation under these conditions.[16] In recent times,
specialized reactors have been developed to perform the cat-
alyst-free selective reduction of terminal olefins by using
hydrazine hydrate and molecular oxygen at high tempera-
ture and pressure in continuous-flow mode.[17]
Since the first application of the Wolff–Kishner reaction
in the synthesis of oxindoles from isatins,[13a] the chemistry
community has used this methodology extensively. A Sci-
Finder survey revealed a total of 120 references to date re-
porting the conversion of various substituted isatins into
oxindoles under these conditions. To the best of our knowl-
edge, there is only one report of a Wolff–Kishner reduction
on a N-ene-/yne-substituted isatin in the chemical litera-
ture.[18] Recently, while describing the synthesis of the hodg-
kinsine and hodgkinsine B alkaloids, Willis et al. reported
the synthesis of N-allyloxindole from N-allylisatin (1a) in
only 20% yield (reported in the Supporting Information)
by using hydrazine hydrate.[18] The reasons behind such a
poor yield were not discussed in the paper. On the basis of
our results (see below), we suspect the loss in yield could
be caused by the reduction of the allyl group under these
conditions. It is quite possible that other researchers may
have faced a similar challenge while attempting to prepare
Introduction
The indolin-2-one or oxindole structural motif is consid-
ered to be an important ring system in heterocyclic chemis-
try owing to its presence in a wide variety of natural prod-
ucts and biologically active compounds.[1] Substituted and
unsubstituted oxindoles also serve as crucial synthetic pre-
cursors for the synthesis of highly desirable indole-based
heterocycles and alkaloids.[2] In the recent past, there has
been considerable effort devoted to the development of an
efficient and general synthesis of substituted oxindoles.
Some of the synthetic strategies include cyclization of o-
aminophenylacetic acid derivatives, oxidative N-hetero-
cyclization of amino alcohols,[3] intramolecular amin-
ation,[4] oxidation of indoles,[5] radical cyclization,[6] inter-
molecular Heck reaction,[7] intramolecular arylation of
amides[8] and amide enolates,[9] the Friedel–Crafts cycliza-
tion of α-halo[10] and α-hydroxy[11] acetanilides, and its
modifications involving C–H functionalization.[12] How-
ever, the classical approach to access substituted oxindoles
is based on the one-step derivatization of isatins under
Wolff–Kishner reduction conditions involving hydrazine hy-
drate.[13–15] This strategy is still widely used and is quite
appealing to synthetic chemists because several substituted
isatins are commercially available and are relatively inex-
pensive. Moreover, the reductive transformation of isatins
to oxindoles is generally a high-yielding process.
There have been previous reports describing the use of
hydrazine hydrate in the selective reduction of unsaturated
[a] Department of Biology and Chemistry, Nipissing University,
North Bay, ON, P1B 8L7, Canada
E-mail: mukundj@nipissingu.ca
www.nipissingu.ca
[b] Department of Chemistry, Birla Institute of Technology and
Science,
Pilani, Rajasthan 333031, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402038.
3334
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3334–3336

Tandem Reduction of Oxo and Ene/Yne Functionalities
N-alkenyl/alkynyloxindoles from the corresponding isatins, allylation of isatin presumably proceeds in near-quantitative
and the undesired results were never reported. In this com- yield, and we suspect the bulk of the loss in the yield might
munication, we report the tandem reduction of oxo- and N- occur in the reduction step, as our results show that the allyl
ene-/yne-substituted isatins to oxindole derivatives, which group is prone to reduction under these conditions (Table 1,
offers novel insight into the scope of the Wolff–Kishner entry 1).
procedure. The reaction is performed under catalyst-free re-
Table 1. Tandem reduction of oxo- and ene-/yne-substituted isatins
by using hydrazine hydrate.[a]
fluxing conditions in the presence of hydrazine hydrate
(25% in H2O). We believe these counterintuitive results will
be of significant importance to the synthetic and medicinal
chemistry community.
Results and Discussion
Entry Substrate
Product
Time Yield[b]
RЈ
R
RЈ
R
[h]
[%]
Several substituted isatins were obtained from commer-
cial sources and were converted into N-(2-alkenyl)/prop-
argyl derivatives 1a–n in quantitative yields by using rea-
gents such as allyl bromide, prenyl bromide, cinnamyl
bromide, and propargyl bromide following a published pro-
cedure.[19] These substitutions are important as such and
are also aptly suited for further chemical manipulations. In-
spired by previous reports of the Wolff–Kishner procedure
for the preparation of oxindoles from isatins, we initially
subjected N-allylisatin (1a) to an excess amount of hydraz-
ine hydrate at reflux temperature (115 °C).[14] Clean conver-
sion of the reactant to the product was evidenced by TLC
analysis. The NMR spectroscopic data of the isolated prod-
uct revealed that along with the C3 oxo group of isatin the
allyl group was also reduced efficiently to deliver 1-propyl-
2-oxindole (2a). If the temperature of the reaction was low-
1
2
3
4
5
6
7
8
1a
H
allyl
2a
H
propyl
4
4
4
5
4
83
81
80
78
80
75
73
71
71
52
89
71
70
68
1b CH3 allyl
1c Cl
1d Br
1e
1f
1g CH3 cinnamyl 2g CH3 3-phenylpropyl 14
1h Cl
1i
1j
1k
1l
2b CH3 propyl
2c Cl
2d Br
allyl
allyl
allyl
propyl
propyl
propyl
F
H
2e
F
H
cinnamyl 2f
3-phenylpropyl 14
cinnamyl 2h Cl
cinnamyl 2i
NO2 cinnamyl 2j
3-phenylpropyl 14
3-phenylpropyl 14
9
F
F
10
11
12
13
14
NH2 3-phenylpropyl
H
H
4
24
4
4
4
H
H
prenyl
propargyl 2a
2k
prenyl
propyl
1m CH3 propargyl 2b CH3 propyl
1n Cl propargyl 2c Cl propyl
[a] Reaction conditions: Isatin (30 mg), NH2NH2·H2O (25%,
2 mL), reflux. [b] Yield if isolated product.
Next, isatins 1l–n possessing an alkyne group were ex-
ered to 80 °C, the reaction did not go to completion. A posed to similar conditions. Remarkably, these propargyl-
significant amount of the starting material remained unre- substituted isatins also underwent a tandem reduction to
acted in the reaction mixture even after 48 h of heating. produce 1-propyl-2-oxindoles quite efficiently (Table 1, en-
Subsequently, we settled with the reflux temperature and tries 12–14). Encouraged by these results, we subsequently
decided to investigate in detail the reduction of N-(2-alk- attempted to scale up the reaction from milligram scale to
enyl)/propargylisatins possessing differently substituted un- gram quantities. We were quite happy to find that the reac-
saturated carbon–carbon bonds by using hydrazine hydrate. tion could be scaled up without any difficulty. A typical
As shown in Table 1, the tandem reduction of the C3 example of scale-up conditions is the following: 1 g of N-
ketone and the olefinic group proceeded quite smoothly for allylisatin (1a) was heated at reflux in 30 mL of hydrazine
isatins bearing monosubstituted and disubstituted unsatu- hydrate (25%), which resulted in 0.81 g of 1-propyl-2-ox-
rations. The yields of the isolated products in all cases were indole (2a, 87%) in 4 h.
found to be high except for nitro-substituted isatin 1j. Inter-
We further proceeded to investigate the reduction of
estingly, the nitro group along with the oxo and olefin func- compounds having a substitution makeup of oxo– and
tionalities also underwent reduction to afford 5-amino-1-(3- carbon–carbon unsaturations, analogous to the isatins de-
phenylpropyl)indolin-2-one (2j) in 57% yield. Although the scribed above by using hydrazine hydrate (Scheme 1). Inter-
reduction of nitroarenes by using hydrazine hydrate has estingly, such compounds, that is, 2-methoxy-6-(prop-2-
been previously reported, the use of an iron source appears ynyloxy)benzaldehyde (3), underwent condensation with
to be a necessary condition to catalyze the reduction pro- hydrazine to produce aldazine 4 under the reaction condi-
cess.[20] Furthermore and quite surprisingly, selective re- tions. Notably, the alkyne functionality of the propargyl
duction of the C3 oxo group was observed for N-prenyl- group of 3 was not reduced under these conditions, but the
isatin (1k, a trisubstituted carbon–carbon unsaturation; entire group was lost during the process (Scheme 1). The
Table 1, entry 11) to produce 1-prenyl-2-oxindole (2k). spectroscopic data of 4 was found to be in agreement with
Even after 24 h of refluxing, the olefin group of 1k was not the literature report.[21]
reduced under these reaction conditions. The yield (20%)
It appears from our results that the tandem reduction of
for the synthesis of related compound N-allyloxindole by the oxo and ene/yne functionalities by using hydrazine is
Willis et al. was reported to be over two steps starting from unique to N-(2-alkenyl)/propargylisatins, for which the re-
isatin (N-allylation followed by hydrazine-mediated re- duction of the C3 oxo group involves the well-known
duction of the C3 oxo group). Among the two steps, the N- Wolff–Kishner mechanism, and the reduction of the olefinic
Eur. J. Org. Chem. 2014, 3334–3336
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3335

M. Jha, G. M. Shelke, A. Kumar
SHORT COMMUNICATION
[1] J. P. MacDonald, J. J. Badillo, G. E. Arevalo, A. Silva-García,
A. K. Franz, ACS Comb. Sci. 2012, 14, 285–293, and references
cited therein.
[2] For selected examples, see: a) B. Robinson, The Alkaloids (Ed.:
R. H. F. Manske), Academic Press, New York, 1967, vol. 10,
p. 383; b) E. Coxworth, The Alkaloids (Ed.: R. H. F. Manske),
Academic Press, New York, 1965, vol. 8, p. 27; c) A. Fensome,
W. R. Adams, A. L. Adams, T. J. Berrodin, J. Cohen, C. Husel-
ton, A. Illenberger, J. C. Kern, V. A. Hudak, M. A. Marella,
E. G. Melenski, C. C. McComas, C. A. Mugford, O. D.
Slayden, M. Yudt, Z. Zhang, P. Zhang, Y. Zhu, R. C. Win-
neker, J. E. Wrobel, J. Med. Chem. 2008, 51, 1861–1873; d) P.
Li, S. L. Buchwald, Angew. Chem. Int. Ed. 2011, 50, 6396–6400;
Angew. Chem. 2011, 123, 6520–6524.
Scheme 1. Reaction of hydrazine hydrate with 2-methoxy-6-(prop-
2-ynyloxy)benzaldehyde (3).
group is facilitated by the in situ formation of a diimide
(created by the aerobic oxidation of hydrazine hydrate),
which is consistent with the previously reported mecha-
nism.[16] Currently, we are actively evaluating the full scope
of this mechanism.
[3] K. Fujita, Y. Takahashi, M. Owaki, K. Yamamoto, R. Yamag-
uchi, Org. Lett. 2004, 6, 2785–2788.
[4] H. Tanabe, J. Ichikawa, Chem. Lett. 2010, 39, 248–249.
[5] a) M. P. J. van Deurzen, F. van Rantwijk, R. A. Sheldon, J.
Mol. Catal. B 1996, 2, 33–42; b) T. Krieg, S. Hüttmann, K.
Mangold, J. Schrader, D. Holtmann, Green Chem. 2011, 13,
2686–2689; c) D. I. Perez, M. M. Grau, I. W. C. E. Arends, F.
Hollmann, Chem. Commun. 2009, 6848–6850; d) C. Bai, Y. Ji-
ang, M. Hu, S. Li, Q. Zhai, Catal. Lett. 2009, 129, 457–461.
[6] a) W. Cabri, I. Candiani, M. Colombo, L. Franzoi, A. Bede-
schi, Tetrahedron Lett. 1995, 36, 949–952; b) K. Jones, J. Wilk-
inson, R. Ewin, Tetrahedron Lett. 1994, 35, 7673–7676; c) K.
Jones, C. McCarthy, Tetrahedron Lett. 1989, 30, 2657–2660; d)
W. R. Bowman, H. Heaney, B. M. Jordan, Tetrahedron Lett.
1988, 29, 6657–6660.
[7] a) Y. Donde, L. E. Overman, Catalytic Asymmetric Synthesis
2nd ed. (Ed.: I. Ojima), Wiley, New York, 2000, chapter 8G,
and references cited therein; b) M. Mori, Y. Ban, Tetrahedron
Lett. 1976, 17, 1807–1810; c) M. Mori, Y. Ban, Tetrahedron
Lett. 1979, 20, 1133–1136.
[8] A. Correa, S. Elmore, C. Bolm, Chem. Eur. J. 2008, 14, 3527–
3529.
Conclusions
In conclusion, the reduction of N-(2-alkenyl)/proparg-
ylisatins by using hydrazine hydrate (25% in H2O) led to
N-alkyloxindoles. This is an unprecedented example of a
tandem reduction of two functionalities (i.e., oxo group and
alkene/alkyne) present in isatin under catalyst-free condi-
tions at ambient pressure. The reaction offers clean conver-
sion of the reactants into products in excellent yields, which
can be easily scaled up to gram quantities. As an added
advantage, the N-(2-alkenyl)/propargylisatins can poten-
tially be further chemically manipulated (e.g., chain elong-
ation by using the alkyne functionality) to prepare diversely
substituted oxindoles. The observed counterintuitive double
reduction provides further insight into the full scope of the
Wolff–Kishner procedure to prepare substituted 2-oxind-
oles.
[9] a) S. Lee, J. F. Hartwig, J. Org. Chem. 2001, 66, 3402–3415; b)
K. H. Shaughnessy, B. C. Hamann, J. F. Hartwig, J. Org.
Chem. 1998, 63, 6546–6553.
[10] A. H. Beckett, R. W. Daisley, J. Walker, Tetrahedron 1968, 24,
6093–6109.
[11] D. Ben-Ishai, N. Peled, I. Sataty, Tetrahedron Lett. 1980, 21,
569–572.
[12] E. J. Hennessy, S. L. Buchwald, J. Am. Chem. Soc. 2003, 125,
12084–12085.
Experimental Section
[13] a) D. S. Soriano, J. Chem. Educ. 1993, 70, 332; b) R. J. Sund-
berg, Indoles, Academic Press, London, 1996, p. 17, 152–154.
[14] C. Crestini, R. Saladino, Synth. Commun. 1994, 24, 2835–2841.
[15] M. Jha, T. Chou, B. Blunt, Tetrahedron 2011, 67, 982–989.
[16] a) S. Hünig, H. R. Müller, W. Thier, Angew. Chem. Int. Ed.
Engl. 1965, 4, 271–280; Angew. Chem. 1965, 77, 368–377; b)
D. J. Pasto, R. T. Taylor, Org. React. 1991, 40, 91.
[17] B. Pieber, S. T. Martinez, D. Cantillo, C. O. Kappe, Angew.
Chem. Int. Ed. 2013, 52, 10241–10244; Angew. Chem. 2013,
125, 10431–10434.
[18] R. H. Snell, M. J. Durbin, R. L. Woodward, M. C. Willis,
Chem. Eur. J. 2012, 18, 16754–16764.
[19] D. Rambabu, S. Kiran Kumar, B. Yogi Sreenivas, S. Sandra, A.
Kandale, P. Misra, M. V. Basaveswara Rao, M. Pal, Tetrahe-
dron Lett. 2013, 54, 495–501.
General Procedure for the Synthesis of Substituted Oxindoles by
using Hydrazine Hydrate: N-(2-Alkenyl)/propargylisatin 1 (0.03 g)
was mixed with hydrazine hydrate (25%, 2 mL) and heated at
115 °C (see Table 1 for the reaction time). Upon completion of the
reaction (as evidenced by TLC), the excess amount of hydrazine
hydrate was evaporated under reduced pressure, and the residue
was subjected to flash column chromatography (silica gel; hexanes/
ethyl acetate, 96:04) to give 1-alkyl-2-oxindole 2.
Supporting Information (see footnote on the first page of this arti-
cle): Spectroscopic data and the copies of the 1H NMR and 13C
NMR spectra for products 1a–n, 2a–k, and 4.
[20] For selected examples, see: a) D. Cantillo, M. M. Moghaddam,
C. O. Kappe, J. Org. Chem. 2013, 78, 4530–4542; b) M. Lau-
winer, P. Rys, J. Wissmann, J. Appl. Catal. A 1998, 172, 141–
148.
[21] V. B. Kurteva, S. P. Simeonov, M. Stoilova-Disheva, Pharma-
col. Pharm. 2011, 2, 1–9.
Acknowledgments
The authors gratefully acknowledge the financial support provided
by the Natural Sciences and Engineering Research Council of
Canada (NSERC), Nipissing University, and the Canada Founda-
tion for Innovation (CFI) to conduct this research.
Received: February 7, 2014
Published Online: April 15, 2014
3336
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3334–3336