Molybdenum hexacarbonyl mediated synthesis of indolin-2-one & azaindolin-2-one under catalyst free conditions

Article abstract of DOI:10.1016/j.tetlet.2015.09.123

Syntheses of indolin-2-ones and azaindolin-2-ones have been realized. The strategy involves the formation of tosylhydrazone from tosylhydrazine and 2-amino aryl or pyridyl aldehydes/ketones which then undergo intramolecular aminocarbonylation to afford indolin-2-ones and azaindolin-2-ones. The generality of the method was demonstrated by synthesizing C3 substituted and unsubstituted indolin-2-one and azaindolin-2-one derivatives.

Full text of DOI:10.1016/j.tetlet.2015.09.123

Tetrahedron Letters 56 (2015) 6370–6372
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Molybdenum hexacarbonyl mediated synthesis of indolin-2-one &
azaindolin-2-one under catalyst free conditions
⇑
Vikas S. Patil, Shyam S. Pal, Ramdas S. Pathare, L. K. K. Reddy, Arunendra Pathak
Jubilant Chemsys Limited, B-34, Sector-58, Noida 201301, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 April 2015
Revised 23 September 2015
Accepted 26 September 2015
Available online 11 October 2015
Syntheses of indolin-2-ones and azaindolin-2-ones have been realized. The strategy involves the
formation of tosylhydrazone from tosylhydrazine and 2-amino aryl or pyridyl aldehydes/ketones which
then undergo intramolecular aminocarbonylation to afford indolin-2-ones and azaindolin-2-ones. The
generality of the method was demonstrated by synthesizing C3 substituted and unsubstituted indolin-
2-one and azaindolin-2-one derivatives.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Azaindole
Aminocarbonylation
Oxindoles
The 2-oxindole is present as a core nucleus in a number of bio-
logically active natural products, drug molecules, and agrochemi-
cals.1 The significance of 2-oxindole in drug discovery has been
well established as a number of drugs having this nucleus are
already in the market for treatment of various diseases.2 For exam-
ple, Sunitinib (Fig. 1) has been approved and marketed for the
treatment of renal cell carcinoma and Imatinib resistant GIST;
whereas Toceranib phosphate (Fig. 1) is used for the treatment of
canine cutaneous mast cell tumors.2
bonylation of tosylhydrazone with Mo(CO)6 has been reported by
Reddy and co-workers (Scheme 1).10
To the best of our knowledge there is no report for the synthesis
of indolin-2-one or azaindolin-2-one using catalyst free
intramolecular aminocarbonylation strategy.
The synthesis commenced with the formation of tosylhydrazone
(2) of 2-aminobenzaldehyde (1).11 The resulting tosylhydrazone
was dissolved in dioxane and heated at 110 °C in the presence of
DBU as a base. We were delighted to observe the formation of indo-
lin-2-one (3) in 80% isolated yield12 (Scheme 2).
The significance of oxindoles in chemical and pharmaceutical
industry prompted us to develop a new strategy for its synthesis.
The most commonly used method employ cyclization strategy,3
derivatization of heterocycle,4 metal-catalyzed cyclocarbonyla-
tions,5 intramolecular Heck couplings of 2-haloacryloylanilides6
and photochemical methods.7 Although most of these methods
are widely used for the generation of oxindoles, limitations remain
because of functional group compatibility, expensive metal cata-
lyst, and prolonged reaction time. Recently ultrasound promoted
clay catalyzed synthesis of oxindoles has been reported.8 However;
this method has practical limitations at a higher scale and remains
restricted only to unsubstituted C3 oxindoles. We proposed to
carry out the synthesis of indolin-2-one and 2-azaindolin-2-one
from tosylhydrazone of 2-aminobenzaldehyde and 2-aminopy-
ridine-3-carbaldehyde, respectively, via intramolecular aminocar-
bonylation in the presence of Mo(CO)6. The tosylhydrazone is a
versatile synthetic intermediate and gained special attention after
the discovery of Barluenga boronic acid coupling (BBA) reaction
under metal free conditions.9 Recently, a palladium free aminocar-
This result was particularly encouraging, as we obtained yields
comparable to the intermolecular aminocarbonylation10 that
employed conventional heating. Next, we screened a variety of sol-
vents and bases and results have been summarized in Table 1.
The solvents did not have much effect on the yields but the nat-
ure of the base had a significant effect. Among DBU, DIPEA, KOtBu,
and Cs2CO3 only DBU furnished the desired product in satisfactory
yields (entries 1–4). With other bases the conversion was either
slow or afforded unwanted products. The optimized reaction
conditions were next applied to tosylhydrazone (5) which was
O
O
N
N
N
H
N
H
F
F
N
H
N
H
O
.H PO
3
O
4
N
H
N
H
Toceranib phosphate
Sunitinib
⇑
Corresponding author.
Figure 1. 2-Oxindole based drug.
http://dx.doi.org/10.1016/j.tetlet.2015.09.123
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

V. S. Patil et al. / Tetrahedron Letters 56 (2015) 6370–6372
6371
Table 2
RNH2, Et4NCl
DBU, Mo(CO)6
O
R1
Synthesis of indolin-2-ones and azaidolin-2-ones
R1
Ar
NHTs
NHR
R1
Yielda (%)
Ar
Entry
1
Tosylhydrazone
Product
Dioxane
Microwave
110 oC
NNHTs
NH2
O
O
N
H
NHTs
Base
55
53
Br
Br
Ar
Br
Br
2a
2b
7
R
N2
Mo(CO)6
Ar
NNHTs
NH2
2
3
RNH-Mo(CO)5
O
N
H
R
Et4NCl
NH2
8
O
R1
Ar
Mo(CO)4RNH
R1
R1
Ar
NNHTs
O
Mo(CO)3RNH
NHR
65
N
Ar
NH2
H
2c
9
Scheme 1. Reddy and co-workers work and proposed mechanism.
Cl
F
Cl
F
NNHTs
NH2
O
O
4
5
50
55
N
H
2d
10
TsNHNH2,
O
NNHTs
NH2
H
N
Dioxane,
90 oC, 1h
DBU, Mo(CO)6,
110 oC, 1h
Ts
N
N
O
H
2e
11
N
H
NH2
NH2
NNHTs
NH2
3
O
2
1
80% yeild
N
H
6
7
8
60
56
52
Scheme 2. Synthesis of indolin-2-one.
F
F
2f
F
F
12
NNHTs
NH2
O
Table 1
Effect of solvent and base
N
H
13
2g
Entry
Solvent
Base
Time (h)
Yielda (%) of 3
NNHTs
NH2
O
O
1
2
3
4
5
6
7
Dioxane
THF
Toluene
DME
Dioxane
Dioxane
Dioxane
DBU
DBU
DBU
DBU
DIPEA
Cs2CO3
KOtBu
1.0
1.0
1.0
1.0
1.0
1.0
1.0
80
75
72
76
N
H
14
2h
Major starting material
No reactionb
NNHTs
NH2
No reactionb
9
56
53
N
H
a
Isolated yield.
15
2i
b
Starting material consumed but desired product was not formed.
Br
F
Br
F
NNHTs
NH2
O
10
N
N
N
16
H
5a
TsNHNH2,
O
H
Dioxane,
DBU, Mo(CO)6,
110 oC, 1h
Ts
N
O
90 oC, 1h
N
N
H
N
NNHTs
NH2
O
11
12
50
57
N
NH2
N
NH2
6
60%
N
H
N
N
17
5
4
5b
Scheme 3. Synthesis of azaindolin-2-one.
NNHTs
NH2
O
N
N
5c
N
H
obtained by treating 2-amino pyridine carbaldehyde (4) with
tosylhydrazine (Scheme 3). The reaction afforded azaindolin-2-
one 6, but the yield (60%) was lower as compared to indolin-2-
one 3.
18
NNHTs
NH2
O
13
54
N
N
N
H
Finally, the optimized conditions were applied to synthesize a
variety of substituted indolin-2-one and azaindolin-2-one deriva-
tives.13 The results have been summarized in Table 2.
As depicted in Table 2, a variety of indolin-2-ones and azain-
dolin-2-ones were successfully synthesized. Attempt to synthesize
the C3 phenyl substituted indolin-2-one (20) from corresponding
2j was not successful. This may be attributed to steric factors aris-
ing from the presence of the phenyl group, thereby interfering with
the intramolecular aminocarbonylation. In a separate experiment,
benzyl amine was added to the reaction mixture (Scheme 4) which
failed to afford the intermolecular aminocarbonylation product 21.
This clearly indicates the involvement of other factors along with
steric factor.
5d
19
14
0
NNHTs
NH2
O
N
H
2j
Isolated yield.
20
a
In conclusion, we have developed a very efficient and catalyst
free method for the synthesis of substituted indolin-2-one and

6372
V. S. Patil et al. / Tetrahedron Letters 56 (2015) 6370–6372
3. (a) Sundberg, R. J. In Indoles; Academic Press: London, 1996; Vol. 17, p. 152; (b)
Ph
NH
Ph
DBU, Mo(CO)6,
110 oC, 1h
Ph
Hardegger, E.; Corrodi, H. Helv. Chim. Acta 1956, 39, 514–517; (c) Cabri, W.;
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Padwa, A.; Kuethe, J. T. J. Org. Chem. 1998, 63, 4256–4268; (k) Kuethe, J. T.;
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H
N
N
Ts
O
NH2
NH2
Ph
NH2
21
2j
Scheme 4. Intermolecular aminocarbonylation.
azaindolin-2-one derivatives. This reaction does not require any
microwave or ultrasound and can be used for large scale synthesis
using the conventional heating. Further studies with the synthesis
of the C3 phenyl substituted indolin-2-one are in progress.
6. Arumugam, V.; Routledge, A.; Abell, C.; Balasubramanian, S. Tetrahedron Lett.
1997, 38, 6473–6476.
Acknowledgment
7. Goehring, R. R.; Sachdeva, Y. P.; Pisipati, J. S.; Sleevi, M. C.; Wolfe, J. F. J. Am.
Chem. Soc. 1985, 107, 435–443.
8. Dandia, A.; Bhati, D. S.; Jain, A. K.; Sharma, G. N. Ultrason. Sonochem. 2011, 18,
We are extremely thankful to Jubilant Chemsys management
for providing financial support and analytical facilities for the
execution of this research work.
1143–1147.
´
´
9. (a) Barluenga, J.; Tomas-Gamasa, M.; Aznar, F.; Valdes, C. Nat. Chem. 2009, 1,
494–499; (b) Barluenga, J.; Valde´s, C. Angew. Chem., Int. Ed. 2011, 50, 7486–
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Supplementary data
10. Rao, K. P.; Basak, A. K.; Raju, A.; Patil, V. S.; Reddy, L. K. Tetrahedron Lett. 2013,
54, 5510–5513.
11. See the Supporting information page S3–S5, for the synthetic procedure of
tosylhydrazone.
12. The reported yield has been arrived after deducting the impurity appearing in
NMR & LCMS.
Supplementary data (experimental detail, reaction conditions
and characterisation of products) associated with this article can
be found, in the online version, at http://dx.doi.org/10.1016/j.
tetlet.2015.09.123.
13. General experimental procedure: To a screw cap vial was added tosylhydrazone
(1.0 mmol) in 1, 4-dioxane (5 mL). Then charged tetraethylammonium
bromide (1.0 mmol) followed by the addition of DBU (2.5 mmol) and Mo
(CO)6 (1.0 mmol) at room temperature. The mixture was heated to 110 °C for
1 h. The reaction progress was monitored by using TLC. After consumption of
starting material the reaction mixture was filtered through celite bed and
washed with ethyl acetate. The ethyl acetate layer was washed with water and
brine. The organic phase was dried over sodium sulfate, filtered, and
concentrated under reduced pressure to afford crude compound. The crude
compound was purified flash chromatography on Biotage instrument using
4.0 g snap cartridge and eluted with ethyl acetate in hexane to give indoline-2-
one. 1H NMR (400 MHz, DMSO-d6) d 3.45 (s, 1H), 6.81-6.79 (d, J = 8 Hz, 1H),
6.93–6.89 (t, J = 8 Hz, 1H), 7.20–7.13 (d, J = 8 Hz, 2H), 10.34 (br s, 1H).13C NMR
(100 MHz, DMSO-d6) d 35.7, 109.1, 121.1, 124.3, 125.7, 127.4, 143.6, 176.3. ES-
MS (m/z): 134.2 (M++H).
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