Regioselective oxidation of indoles to 2-oxindoles

Article abstract of DOI:10.1039/c9ob00764d

Facile regioselective oxidation of indoles to 2-oxindoles promoted by sulfuric acid adsorbed on silica gel is reported. The demonstrated practical site-selective heterogeneous oxidation reactions conveniently take place with a broad substrate scope and functional group tolerances. The present oxidation strategy is also employed to accomplish the total synthesis of natural products donaxaridine and donaxarine. On the basis of analytical and spectral data it is evidenced that donaxarine stays in equilibrium with its hydrated ring opened form. The structural features essential for this type of oxidation and plausible mechanism are discussed in brief.

Full text of DOI:10.1039/c9ob00764d

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DOI: 10.1039/C9OB00764D
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Regioselective oxidation of indoles to 2-oxindoles†
Santosh V. Shelara,b and Narshinha P. Argade*,a,b
Received 00th January 20xx,
Accepted 00th January 20xx
Facile regioselective oxidation of indoles to 2-oxindoles promoted by sulfuric acid adsorbed on silica gel is reported. The
demonstrated practical site-selective heterogeneous oxidation reactions conveniently take place with broad substrate
scope and functional group tolerances. The present oxidation strategy is also employed to accomplish total synthesis of
natural products donaxaridine and donaxarine. On the basis of analytical and spectral data it is evidenced that the
donaxarine stays in equilibrium with its hydrated ring opened form. The structural features essential for such type of
DOI: 10.1039/x0xx00000x
oxidation
and
plausible
mechanism
are
discussed
in
brief.
O
Introduction
O
F
HN
N
N
H
HN
N
Me
The 2-oxindole moiety is present in large number of bioactive
natural and unnatural products, clinically used drugs and drug
intermediates (Figure 1).1 Regioselective oxidations of indoles to 2-
oxindoles and 3-oxindoles have been very important reactions from
synthetic organic chemistry point of view.2 Several elegant
inorganic, organic and bioorganic reagents for oxidation reactions
of indoles to 2-oxindoles have been reported in the earlier and
contemporary literature and a few selected methods have been
depicted in scheme 1.3 Application of an appropriate oxidizing
reagent and the development of suitable reaction conditions for
smooth transformation of variety of indoles to the corresponding 2-
oxindole derivatives is a challenging task from formed products’
reactivity and overall stability point of view.1‒3 In continuation of
our studies on total synthesis of recently isolated bioactive natural
products,4 we attempted the concentrated sulfuric acid adsorbed
on silica gel facilitated intramolecular cyclization of one of the
indole bearing compound and noticed the unplanned effective
formation of corresponding 2-oxindole derivative. In this context
we herein report simple and efficient sulfuric acid persuaded
regioselective oxidation of indoles to 2-oxindoles and its application
in synthesis of natural products (Tables 1 and 2; Schemes 2 and 3).
N
H
O
N
O
H
Indolidan
Sunitinib (antitumor)
(antihypertensive)
Me
N
H
O
N
R
OMe
N
N
O
H
H
H
MeO2C
Coerulescine (R = H)
Horsfiline (R = OMe)
Corynoxine (sedative)
F
Cl
O
N
H
H
O
N
O
H
HN
HN
Cl
N
H
O
N
H
OMe
NITD609
Spirotryprostatin A
(anticancer)
(antimalarial)
Fig. 1 Representative drugs and natural products comprising of 2-
oxindole moiety1
Results and discussion
The reaction of indole (1a, 1.00 g) with concentrated sulfuric acid
adsorbed on silica gel (60‒120 mesh, 1.00 g) in dichloromethane at
25 °C was monitored by TLC. The above specified reaction at the
end of ten hours selectively furnished the corresponding pure 2-
oxindole (2a) in 78% yield (Table 1; entry 1). However, the same
reaction in 1,2-dichoroethane as a solvent was slow and furnished
the 2-oxindole (2a) only in 62% yield (Table 1, entry 2). The change
of silica gel mesh size to 100‒200 and 230‒400 mesh for adsorption
of sulfuric acid and repetition of same reaction in dichloromethane
did not show any noticeable changes in reaction time and yield. The
recycling and reuse of recovered sulfuric acid adsorbed on silica gel
reagent slowed down the rate of oxidation reaction due to nearly
35% loss of sulfuric acid (by weight and NaOH titration) during first
use. In a control experiment, direct reaction of indole (1a) with
concentrated sulfuric acid in dichloromethane resulted in complete
decomposition. The substrates N-methylindole (1b) and N-
tosylindole (1c) on treatment with H2SO4 adsorbed on SiO2
remained unreacted and the expected 2-oxindole products 2b and
2c were not formed indicating that the presence of hydrogen atom
on indole nitrogen is necessary for the progression of oxidation
(Table 1, entries 3 and 4). The reaction of N-Boc protected indole 1d
a. Division of Organic Chemistry, National Chemical Laboratory (CSIR), Pune 411
008, India. E-mail: np.argade@ncl.res.in
b. Academy of Scientific and Innovative Research (AcSIR), New Delhi 110 025, India.
†.Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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with H2SO4 adsorbed on SiO2 resulted in complete decomposition of acid; which in the presence of dissolved oxygen transforms back to
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reaction mixture mostly via the acid catalyzed Boc-deprotection sulfuric acid and also partly degrades into sulfur dioxide. At this
DOI: 10.1039/C9OB00764D
route (Table 1, entry 5). The indole based amines 1e-h on reaction stage we decided to systematically study the substrate scope,
with H2SO4 adsorbed on SiO2 also remained completely unreacted functional group tolerance and application of present indole to 2-
possibly due to the formation of corresponding salts by protonation oxindole transformation protocol for the synthesis of unnatural and
of free amine groups (Table 1, entry 6).
natural products (Table 2, Scheme 3). The indole-3-acetic acid (1i)
on treatment with H2SO4 adsorbed on SiO2 underwent facile
oxidation and provided the desired natural product 2-oxindole-3-
acetic acid (2i) (isolated from Zea mays seedlings)5 in quantitative
Me
Me
O
NBS, AcOH
(1)
H2SO4 (ref.3a)
N
N
H
H
H2SO4
Proton
DMSO, HCl
H
O
on SiO2
capture
(2)
N
N
H
O
S
OH
N
H
O
S
H2O (ref. 3b)
N
O
H
N
H
O
O
H
O
O
A
B
]
[
]
[
1a
Indole (
)
OH
HO
OH
HO
OH
Zea mays
(3)
O
O
seedlings (ref. 3c)
Reductive elimination of
sulfurous acid on SiO2
Addition of
oxyanion
N
H
N
H
N
H
O
S
OH
N
H
O
HO
H
O
O
O
O
DBU, toluene
40 ºC (ref. 3d)
C
[
]
2a
2-Oxindole (
)
(4)
(5)
N
N
O
O
Ac
Ac
HO
HO
Scheme 2 Plausible mechanism for H2SO4 adsorbed on SiO2 induced
regioselective oxidation of indole to 2-oxindole.
Chloroamine-B, NaOH
H2O, 25 ºC (ref. 3e)
N
H
N
H
Table 1 Study of H2SO4 adsorbed on SiO2 facilitated regioselective
oxidation of indole derivatives.
Pyridium bromide
(6)
perbromide, AcOH
(ref. 3f)
N
H
N
H
O
reaction
conditionsa,b
2a-h
(% yield)
products
starting materials
entry
1a-h
OMe
OMe
H2SO4 on SiO2
DCM, 25 ºC, 10 h
1
m-CPBA, DCM
(7)
N
H
N
O
O
25 ºC (ref. 3g)
MeO
N
O
MeO
N
H
1a
CO2Me
2a
2a
CO2Me
(78%)
H2SO4 on SiO2
ClCH2CH2Cl
25 ºC, 18 h
Chloroperoxiase
H2O2 (ref. 3h)
2
3
4
5
(8)
N
H
N
H
N
H
N
H
O
O
O
1a
(62%)
Mn(III)porphyrin
(9)
H2SO4 on SiO2
DCM, 25 ºC, 24 h
H2O2, CH3CN (ref. 3i)
N
H
N
H
N
O
N
Me
Me
1-Floro-1,2-benziodoxol-3-
c
(1H)-one
1b
2b
2c
(10)
(not formed)
1,4-dioxane, H2O (1:5)
(ref. 3j)
N
R
N
R
H2SO4 on SiO2
DCM, 25 ºC, 24 h
N
Ts
N
O
Ts
c
1c
Scheme 1 Selected chemical and biomimetic oxidation reactions of
(not formed)
indoles to 2-oxindoles.
H2SO4 on SiO2
DCM, 25 ºC, 24 h
On the basis of results summarized in Table 1; a plausible
reaction mechanism for H2SO4 adsorbed on SiO2 driven oxidation of
indole (1a) to oxindole (2a) has been illustrated in scheme 2.
Mechanistically, the indole (1a) dissolved in dichloromethane
penetrates in SiO2 cavities and complexes with adsorbed H2SO4
through hydrogen bonding to form the intermediate A. An
intermediate A captures the proton via delocalization of nitrogen
lone pair to form the iminium salt B. Addition of oxyanion to the
formed reactive iminium double bond in a concerted/stepwise
fashion results in another intermediate C with overall addition of
sulfuric acid across the carbon‒carbon double bond in an indole
moiety. Finally oxidation of indole to 2-oxindole takes place via
reductive elimination of sulfurous acid (HO-SO-OH) involving the
hexavalent to tetravalent state transformation of sulfur. Overall the
oxidant is sulfuric acid and it gets converted into unstable sulfurous
N
Boc
1d
N
O
Boc
d
2d
(not obtained)
H2SO4 on SiO2
DCM, 25 ºC, 24 h
6
NR1R2
NR1R2
N
H
N
O
H
c
1e
1f
1g
1h
2e h
- (not formed)
(R1 = R2 = H)
(R1 = H, R2 = Me)
(R1 = R2 = Me)
(R1 = H, R2 = CH2Ph)
a One mL of conc. H2SO4 was adsorbed on ten gram of SiO2 (60‒120
b
mesh) and used in weight: weight ratio for all starting materials;
monitored by TLC; c starting material recovered; d decomposition
2 | J. Name., 2012, 00, 1-3
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Table 2 H2SO4 Adsorbed on SiO2 induced regioselective oxidation of very expensive pure acid 2i in 82% yield. The analytical and spectral
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indoles to 2-oxindoles
data obtained for 2-oxindole-3-acetic acid (2i) were in complete
DOI: 10.1039/C9OB00764D
agreement with the reported data.5,6 2-Oxindole-3-acetic acid (2i)
on treatment with diazomethane afforded the corresponding ester
2j in 94% yield. However the methyl indole-3-acetate (1j) on
reaction with H2SO4 adsorbed on SiO2 resulted in formation of
complex mixture and did not provide the expected methyl 2-
oxindole-3-acetate (2j) (Table 2, entry 3). Amide bearing indoles 1k
and 1l on reaction with H2SO4 adsorbed on SiO2 provided the
corresponding 2-oxindoles 2k and 2l in 71% and 82% yields
respectively (Table 2, entries 4 and 5). The cyclic imide bearing
indoles 1m-q on reaction with H2SO4 adsorbed on SiO2 also
delivered the desired 2-oxindoles 2m-q in 69-81% yields (Table 2,
entries 6‒10). Amic ester bearing indoles 1r and 1s on reaction with
H2SO4 adsorbed on SiO2 directly furnished the corresponding cyclic
imides bearing 2-oxindoles 2m and 2n in 63% and 68% yields
respectively via in situ intramolecular cyclization followed by
oxidation pathway (Table 2, entries 11 and 12). Carbamate bearing
indoles 1t and 1u on reaction with H2SO4 adsorbed on SiO2
delivered the corresponding 2-oxindoles 2t and 2u in 78% and 82%
yields respectively (Table 2, entries 13 and 14). The results
summarized in table 2 clearly revealed that the present oxidation
reactions are friendly with carboxylic acid, amide, cyclic imide and
carbamate functional groups. On the basis of obtained results we
feel that the sulfuric acid adsorbed on silica gel reagent will be quite
friendly with several other non-amine substituents and functional
groups bearing substrates.
products 2a,i-q,t,u
reaction conditionsa
starting materials
entry
(% yield)
1a,i-u
H2SO4 on SiO2
DCM, 25 ºC, 10 h
1
N
H
1a
N
O
H
2a
(natural product, 78%)
OH
OH
O
H2SO4 on SiO2
DCM, 25 ºC, 16 h
2
O
N
H
N
O
H
1i
2i
(natural product, 82%)
OMe
OMe
O
H2SO4 on SiO2
DCM, 25 ºC, 8 h
3
O
N
H
N
O
H
b
1j
2j
(not obtained)
H
N
H
N
Me
Me
Ph
H2SO4 on SiO2
4
5
DCM, 25 ºC, 18 h
O
O
O
N
H
N
H
O
O
O
1k
2k
2l
(71%)
H
N
H
N
Ph
H2SO4 on SiO2
DCM, 25 ºC, 12 h
O
N
H
N
H
1l
(82%)
O
O
N
N
N
H2SO4 on SiO2
DCM, 25 ºC, 16 h
6
7
O
O
N
H
N
H
1m
2m
2n
(73%)
O
O
O
N
N
H2SO4 on SiO2
DCM, 25 ºC, 14 h
O
O
The natural products donaxaridine (4) and donaxarine (6) were
isolated from Arundo donax in 1976.7 Till date five different total
syntheses of donaxaridine (4) have been accomplished employing
several elegant strategies.8 Total synthesis of natural products 4
and 6 was planned starting from the obtained carbamate bearing 2-
oxindole 2u as a potential precursor (Table 2, entry 14; Scheme 3).
The compound 2u on reaction with molecular oxygen in the
presence of t-BuOK underwent smooth benzylic hydroxylation and
delivered the desired product 3 in 86% yield.9 The cleavage of
carbamate in compound 3 with TBAF in THF or 2 N HCl in methanol
under reflux conditions was not successful and starting material
remained unreacted. However, diethylenetriamine assisted
carbamate cleavage10 of compound 3 in a sealed tube at 120 °C
furnished the desired donaxaridine (4) in 91% yield. The analytical
and spectral data obtained for donaxaridine (4) were in complete
agreement with the reported data.7,8 Donaxaridine (4) on treatment
with acetaldehyde in CH2Cl2/CHCl3 at 25°C/reflux conditions always
resulted in a mixture of geminal-aminohydrin intermediate 5B and
the natural product donaxarine (6) in 76% yield. As expected the
TLC of reaction mixture revealed that donaxarine (6) has a higher
Rf-value and geminal-aminohydrin intermediate 5B has a lower Rf-
value than the starting material donaxaridine (4). All our attempts
to separate the above specified mixture of products by using silica
gel column chromatography and also by using HPLC were
unsuccessful and always resulted in inseparable mixture of products
5B and 6 in 35:65 ratio (by 1H NMR). Therefore on the basis of
analytical and spectral data it is demonstrated that the donaxarine
(6) always stays in equilibrium with its hydrated ring opened form
5B. Plausibly the formed geminal-aminohydrin intermediate 5B is
stabilized by depicted intramolecular hydrogen bonding in 8-
membered boat-chair conformation11 and the mixture of
compounds 5B and 6 is an example of delicately balanced stability
driven hydration-dehydration equilibrium. Finally, the mixture of
compounds 5B and 6 on reaction with Ac2O/NaOAc exclusively
N
H
N
H
O
1n
(69%)
Me
Me
O
N
H2SO4 on SiO2
DCM, 25 ºC, 16 h
8
9
O
O
N
H
O
N
H
1o
2o
2p
(76%)
OMe
OMe
O
O
N
N
H2SO4 on SiO2
DCM, 25 ºC, 20 h
O
O
N
H
N
H
O
1p
(74%)
O
O
O
O
N
N
N
N
H2SO4 on SiO2
DCM, 25 ºC, 18 h
10
11
O
O
O
O
N
H
O
O
N
H
2q
2m
2n
2t
1q
(81%)
H2SO4 on SiO2
DCM, 25 ºC, 24 h
HN
N
H
N
H
O
O
O
OMe
(63%)
1r
H2SO4 on SiO2
DCM, 25 ºC, 24 h
12
13
14
HN
N
H
N
H
O
O
O
OMe
(68%)
1s
H
N
H
N
OMe
OMe
OMe
H2SO4 on SiO2
DCM, 25 ºC, 12 h
O
N
H
N
H
O
O
1t
(78%)
Me
N
Me
N
OMe
H2SO4 on SiO2
DCM, 25 ºC, 15 h
O
O
N
H
N
H
2u
(82%)
1u
a Monitored by TLC; b decomposition
yield (Table 2, entry 2), which was not very stable to column
chromatographic purifications due to associated stability and
polarity issues. Therefore the formed product was quickly filtrated
through silica gel column using DCM-MeOH as an eluent to obtain
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DOI: 10.1039/C9OB00764D
ARTICLE
Me
N
Me
N
Me
HO
HO
OMe
NHMe
OMe
N
OMe
H2SO4 on SiO2
t-BuOK, O2, toluene
Diethylenetriamine
O
O
O
0-25 ºC, 4 h (86%)
sealed tube, 120 ºC
6 h (91%)
DCM, 25 ºC (82%)
N
H
O
N
O
N
H
N
H
O
H
3
4
)
Donaxaridine (
1u
2u
CH3CHO, DCM
0-25 ºC, 3 h (76%)
Me
Me
Me
Me
Me
H
HO
Me
N
O
N
OH
O
O
O H
N
Me
Ac2O, NaOAc, 25 ºC
8 h (89%)
Dehydrative cyclization (- H2O)
Hydrative ring cleavage (+ H2O)
N
Me
N
O
N
H
O
N
O
N
O
H
H
COCH3
6
5B 6
: = 35:65)
Donaxarine (
)
(Insepareble mixture,
5B
(Boat-chair conformation)
7
5A
Scheme 3 Stepwise oxidations of indole moiety leading to facile synthesis of donaxaridine and donaxarine
formed the N-acyl derivative 7 of donaxarine (6) in 89% yield.
in acetone (15 mL) under vigorous stirring at room temperature.
After 1 h acetone was removed on a rotatory evaporator in vacuo
and the obtained residue was dried by using vacuum pump. A free-
flowing powder of sulfuric acid adsorbed on silica gel was obtained
in quantitative yield (12.87 g). The quantitative loading of sulfuric
acid on silica gel was checked by weight and also by sodium
hydroxide titration.
Conclusions
In summary, we have demonstrated new simple and efficient
method for regioselective oxidation of indoles to 2-oxindoles using
sulfuric acid adsorbed on silica gel as a reagent. It will be useful for
synthesis of broad range of desired bioactive natural and unnatural
oxindoles. A plausible mechanism has been proposed and the
presence of free proton on indole nitrogen atom is essential for
formation of complex with sulfuric acid. The present practical
oxidation reaction induced by heterogeneous reagent nicely
addresses the product stability concerns and functional group
tolerance issues. We also believe that the present protocol has a
scale up potential and will be useful for large scale production of
several oxindole derivatives of commercial interest.
General procedure for oxidation of indoles to 2-oxindoles.
To a stirred solution of indole (1.00 g) in CH2Cl2 (20 mL) was added
sulfuric acid adsorbed on silica gel (1.00 g) at 25 °C and the reaction
was monitored by TLC. The reaction mixture was filtrated and the
filtrate was washed with saturated aq. NaHCO3 (10 mL). The organic
layer was washed with water, brine and dried over Na2SO4.
Concentration of organic layer in vacuo followed by silica gel
(230400 mesh) column chromatographic purification of the
residue by using ethyl acetatepetroleum ether as an eluent
provided the desired 2-oxindole.
Experimental section
General Description
Melting points are uncorrected. The 1H NMR spectra were recorded
on 200 MHz NMR, 400 MHz NMR and 500 MHz NMR spectrometers
using TMS as an internal standard. The 13C NMR spectra were
recorded on 200 NMR (50 MHz), 400 NMR (100 MHz) and 500 NMR
(125 MHz) spectrometers. Mass spectra were taken on MS-TOF
mass spectrometer. HRMS (ESI) were taken on Orbitrap
(quadrupole plus ion trap) and TOF mass analyzer. The IR spectra
were recorded on an FT-IR spectrometer. Column chromatographic
separations were carried out on silica gel (60120 mesh) and
(230400 mesh). Commercially available indole, tryptamine, indole-
3-acetic acid, t-BuOK, sulfuric acid, diethylenetriamine,
acetaldehyde, acetic anhydride and sodium acetate were used.
Indolin-2-one (2a): According to the general procedure and by
using ethyl acetatepetroleum ether (0.5:9.5) as an eluent, 2a was
1
obtained as a brown solid (886 mg, 78%). Mp 128–130 °C, H NMR
(CDCl3, 200 MHz) δ 3.56 (s, 2H), 6.90 (dd, J = 8.2 and 1.0 Hz, 1H),
7.02 (td, J = 7.7 and 1.0 Hz, 1H), 7.17‒7.30 (m, 2H), 8.73 (br s, 1H);
13C NMR (CDCl3, 50 MHz) δ 36.3, 109.8, 122.3, 124.6, 125.3, 127.9,
142.5, 178.0; ESIMS (m/z) 156 [M+Na]+; HRMS (ESI) calcd for
C8H7ONNa 156.0420, found 156.0417; IR (CHCl3)max 3174, 1732,
1687, 1617 cm-1.
2-(2-Oxoindolin-3-yl)acetic acid (2i): According to the general
procedure and by using methanoldichloromethane (0.5:9.5) as an
eluent, 2i was obtained as a white crystalline solid (179 mg, 82%).
Preparation of the sulfuric acid adsorbed on silica gel.
A solution of concentrated sulfuric acid (1.00 mL) in acetone (10
mL) was added to a suspension of silica gel (10.00 g, 60120 mesh)
1
Mp 140–142 °C, H NMR (DMSO-d6, 200 MHz) δ 2.69 (dd, J = 17.0
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ARTICLE
and 7.0 Hz, 1H), 2.90 (dd, J = 17.3 and 4.2 Hz, 1H), 3.50‒3.70 (m, 1H), 3.55‒3.85 (m, 2H), 6.18 (q, J = 1.9 Hz, 1H), 6.86V(idew, JAr=tic7le.O7nHlinze,
DOI: 10.1039/C9OB00764D
1H), 6.81 (d, J = 7.3 Hz, 1H), 6.91 (t, J = 7.4 Hz, 1H), 7.05‒7.30 (m, 1H), 7.01 (td, J = 7.5 and 1.0 Hz, 1H), 7.17 (d, J = 7.7 Hz, 1H), 7.25 (t,
2H), 10.38 (br s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 34.0, 41.8, J = 7.3 Hz, 1H), 8.16 (br s, 1H); 13C NMR (CDCl3, 50 MHz) δ 10.8,
109.2, 121.2, 123.7, 127.8, 129.4, 142.9, 172.3, 178.3; ESIMS (m/z) 28.3, 34.9, 43.8, 109.9, 122.4, 124.0, 127.1, 128.0, 128.6, 141.4,
214 [M+Na]+; HRMS (ESI) calcd for C10H9O3NNa 214.0475, found 145.4, 170.6, 171.5, 179.1; ESIMS (m/z) 271 [M+H]+; HRMS (ESI)
214.0474; IR (Nujol)max 3362, 28002700, 1710 cm-1.
calcd for C15H15O3N2 271.1077, found 271.1074; IR (CHCl3)max 3282,
1708, 1625 cm-1.
N-[2-(2-Oxoindolin-3-yl)ethyl]acetamide (2k): According to the
general procedure and by using ethyl acetatepetroleum ether 3-Methoxy-1-[2-(2-oxoindolin-3-yl)ethyl]-1H-pyrrole-2,5-dione
(4:6) as an eluent, 2k was obtained as a yellow solid (77 mg, 71%). (2p): According to the general procedure and by using ethyl
Mp 130–132 °C, 1H NMR (CDCl3, 500 MHz) δ 1.95 (s, 3H), 2.02‒2.11 acetatepetroleum ether (4:6) as an eluent, 2p was obtained as a
1
(m, 1H), 2.20‒2.29 (m, 1H), 3.42‒3.55 (m, 3H), 6.42 (br s, 1H ), 6.90 white solid (78 mg, 74%). Mp 166–168 °C, H NMR (DMSO-d6, 400
(d, J = 7.7 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), MHz) δ 1.90‒2.02 (m, 1H), 2.07‒2.18 (m, 1H), 3.35‒3.55 (m, 3H),
7.28 (d, J = 7.7 Hz, 1H), 8.65 (br s, 1H); 13C NMR (CDCl3, 125 MHz) δ 3.84 (s, 3H), 5.75 (s, 1H), 6.80 (d, J = 7.6 Hz, 1H), 6.95 (t, J = 7.6 Hz,
23.2, 30.0, 37.2, 44.4, 109.8, 122.7, 124.2, 128.2, 129.2, 141.1, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.26 (d, J = 7.3 Hz, 1H), 10.39 (br s, 1H);
170.5, 180.3; ESIMS (m/z) 241 [M+Na]+; HRMS (ESI) calcd for 13C NMR (DMSO-d6, 100 MHz) δ 28.2, 34.2, 43.0, 59.1, 96.9, 109.4,
C12H14O2N2Na 241.0947, found 241.0943; IR (CHCl3)max 3301, 3012, 121.3, 123.8, 127.7, 128.9, 142.6, 160.8, 165.1, 170.1, 178.2; ESIMS
1710, 1650 cm-1.
(m/z) 287 [M+H]+; HRMS (ESI) calcd for C15H15O4N2 287.1026, found
287.1024; IR (CHCl3)max 3422, 1721, 1676 cm-1.
N-[2-(2-Oxoindolin-3-yl)ethyl]benzamide (2l): According to the
general procedure and by using ethyl acetatepetroleum ether 2-[2-(2-Oxoindolin-3-yl)ethyl]isoindoline-1,3-dione (2q): According
(1:1) as an eluent, 2l was obtained as a brown solid (174 mg, 82%). to the general procedure and by using ethyl acetatepetroleum
Mp 178–180 °C, 1H NMR (DMSO-d6, 500 MHz) δ 1.97 (br s, 1H), 2.13 ether (3:7) as an eluent, 2q was obtained as a brown solid (256 mg,
(br s, 1H), 3.40‒3.60 (m, 3H), 6.84 (d, J = 6.0 Hz, 1H), 6.97 (br s, 1H), 81%). Mp 190‒192 °C, 1H NMR (DMSO-d6, 500 MHz) δ 2.02‒2.15
7.18 (br s, 1H), 7.35 (d, J = 5.4 Hz, 1H), 7.45 (br s, 2H), 7.50 (d, J = 5.3 (m, 1H), 2.20‒2.32 (m, 1H), 3.52 (t, J = 6.9 Hz, 1H), 3.55‒3.67 (m,
Hz, 1H), 7.83 (d, J = 5.3 Hz, 2H), 8.56 (br s, 1H), 10.42 (br s, 1H); 13
C
1H), 3.67‒3.80 (m, 1H), 6.79 (d, J = 9.9 Hz, 1H), 6.86 (t, J = 9.2 Hz,
NMR (DMSO-d6, 125 MHz) δ 30.1, 36.6, 43.3, 109.3, 121.3, 124.2, 1H), 7.10 (t, J = 9.2 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.79 (br s, 4H),
127.2, 127.7, 128.2, 129.5, 131.1, 134.5, 142.6, 166.2, 178.9; ESIMS 10.40 (br s, 1H); 13C NMR (DMSO-d6, 125 MHz) δ 28.0, 34.7, 43.2,
(m/z) 281 [M+H]+; HRMS (ESI) calcd for C17H17O2N2 281.1285, found 109.3, 121.2, 122.9, 123.8, 127.6, 128.9, 131.7, 134.2, 142.7, 167.7,
281.1280; IR (CHCl3)max 3346, 2944, 1711, 1638 cm-1.
178.3; ESIMS (m/z) 307 [M+H]+; HRMS (ESI) calcd for C18H15O3N2
307.1077, found 307.1073; IR (Nujol)max 3380, 1712 cm-1.
1-[2-(2-Oxoindolin-3-yl)ethyl]pyrrolidine-2,5-dione
(2m):
According to the general procedure and by using ethyl Methyl [2-(2-oxoindolin-3-yl)ethyl]carbamate (2t): According to
acetatepetroleum ether (4:6) as an eluent, 2m was obtained as a the general procedure and by using ethyl acetatepetroleum ether
yellow solid (117 mg, 73%). Mp 152–154 °C, 1H NMR (DMSO-d6, 200 (3:7) as an eluent, 2t was obtained as a gummy solid (418 mg, 78%).
MHz) δ 1.56‒2.03 (m, 1H), 2.03‒2.25 (m, 1H), 2.50 (s, 4H), 1H NMR (DMSO-d6, 500 MHz) δ 1.73‒1.90 (m, 1H), 1.90‒2.05 (m,
3.03‒3.65 (m, 3H), 6.82 (d, J = 7.6 Hz, 1H), 6.96 (t, J = 7.5 Hz, 1H), 1H), 3.03‒3.23 (m, 2H), 3.37 (s, 3H), 3.30‒3.45 (m, 1H), 6.82 (d, J =
7.18 (t, J = 7.5 Hz, 1H), 7.30 (d, J = 7.2 Hz, 1H), 10.40 (br s, 1H); 13C 9.2 Hz, 1H), 6.95 (t, J = 9.3 Hz, 1H), 7.17 (t, J = 9.2 Hz, 1H), 7.23 (br s,
NMR (DMSO-d6, 50 MHz) δ 27.2, 27.9, 35.2, 43.1, 109.3, 121.3, 1H), 7.28 (d, J = 8.4 Hz, 1H), 10.39 (br s, 1H); 13C NMR (DMSO-d6,
123.9, 127.8, 129.0, 142.7, 177.5, 178.3; ESIMS (m/z) 259 [M+H]+; 125 MHz) δ 30.6, 37.6, 42.9, 51.3, 109.3, 121.3, 124.1, 127.7, 129.5,
HRMS (ESI) calcd for C14H15O3N2 259.1077, found 259.1074; IR 142.6, 156.7, 178.8; ESIMS (m/z) 257 [M+Na]+; HRMS (ESI) calcd for
(Nujol)max 3272, 1714, 1612 cm-1.
C12H14O3N2Na 257.0897, found 257.0892; IR (Nujol)max 3375, 3141,
1699, 1616 cm-1.
1-[2-(2-Oxoindolin-3-yl)ethyl]-1H-pyrrole-2,5-dione (2n): According
to the general procedure and by using ethyl acetatepetroleum Methyl
methyl[2-(2-oxoindolin-3-yl)ethyl]carbamate
(2u):
ether (4:6) as an eluent, 2n was obtained as a yellow solid (184 mg, According to the general procedure and by using ethyl
1
69%). Mp 124–126 °C, H NMR (CDCl3, 400 MHz) δ 2.20‒2.35 (m, acetatepetroleum ether (4:6) as an eluent, 2u was obtained as a
1
1H), 2.35‒2.50 (m, 1H), 3.52 (br s, 1H), 3.57‒3.71 (m, 1H), 3.71‒3.85 gummy solid (418 mg, 82%). H NMR (CDCl3, 500 MHz) (rotameric
(m, 1H), 6.56 (s, 2H), 6.89 (d, J = 7.3 Hz, 1H), 7.02 (t, J = 6.7 Hz, 1H), mixture) δ 2.07‒2.30 (m, 2H), 2.89 (s, 3H), 3.27‒3.39 (m, 1.50H),
7.19 (t, J = 6.7 Hz, 1H), 7.26 (d, J = 7.3 Hz, 1H), 8.68 (br s, 1H); 13C 3.47 (t, J = 6.1 Hz, 1H), 3.55‒3.72 (m, 3.50H), 6.85‒6.95 (m, 1H),
NMR (CDCl3, 50 MHz) δ 28.1, 34.8, 43.8, 110.0, 122.5, 124.0, 128.1, 7.00‒7.08 (m, 1H), 7.15‒7.42 (m, 2H), 8.70‒9.05 (m, 1H); 13C NMR
128.5, 133.9, 141.5, 170.5, 179.3; ESIMS (m/z) 279 [M+Na]+; HRMS (CDCl3, 125 MHz) δ 28.3, 34.0, 34.6, 43.6, 45.5, 46.2, 52.6, 109.7,
(ESI) calcd for C14H12O3N2Na 279.0740, found 279.0736; IR 122.37, 122.44, 123.9, 124.1, 124.3, 128.0, 128.1, 129.2, 141.66,
(Nujol)max 3382, 1712 cm-1.
141.71, 156.9, 157.0, 179.8, 180.1; ESIMS (m/z) 271 [M+Na]+; HRMS
(ESI) calcd for C13H16O3N2Na 271.1053, found 271.1047; IR
(CHCl3)max 3255, 3012, 2927, 1699, 1618 cm-1.
3-Methyl-1-[2-(2-oxoindolin-3-yl)ethyl]-1H-pyrrole-2,5-dione (2o):
According to the general procedure and by using ethyl
acetatepetroleum ether (1:1) as an eluent, 2o was obtained as a Methyl 2-(2-oxoindolin-3-yl)acetate (2j).
A
solution of
yellow solid (161 mg, 76%). Mp 132‒134 °C, 1H NMR (CDCl3, 200 diazomethane in Et2O was added to a stirred solution of acid 2i (150
MHz) δ 1.98 (d, J = 1.8 Hz, 3H), 2.15‒2.55 (m, 2H), 3.51 (t, J = 5.3 Hz, mg, 0.785 mmol) in methanol (5 mL) until persistence of yellow
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colour. Reaction mixture was stirred at 25 °C for 1 h and for 3 h and the reaction mixture was concentrated ViniewvAarctiucloe .OnTlhinee
DOI: 10.1039/C9OB00764D
concentrated in vacuo. The obtained residue was dissolved in ethyl direct silica gel (60120 mesh) column chromatographic purification
acetate (10 mL) and the organic layer was washed with water, brine of the resulting residue by using ethyl acetatepetroleum ether
and dried over Na2SO4. Concentration of organic layer in vacuo (1:1) as an eluent furnished an equilibrium mixture of natural
followed by silica gel (230400 mesh) column chromatographic product donaxarine (6) and its gem-aminohydrin precursor 5B as a
purification of the residue by using methanoldichloromethane white solid (128 mg, 76%). Mp 176–182 °C, 1H NMR (CDCl3, 400
(0.2:9.8) as an eluent afforded ester 2j as a white crystalline solid MHz) [equilibrium mixture of natural product donaxarine (6) and its
1
(151 mg, 94%). Mp 170–172 °C, H NMR (CDCl3, 500 MHz) δ 2.84 precursor 5B in 65:35 ratio] δ 1.39 (d, J = 5.4 Hz, 1.95H), 1.51 (d, J =
(dd, J = 16.8 and 8.0 Hz, 1H), 3.10 (dd, J = 17.0 and 4.2 Hz, 1H), 3.71 5.4 Hz, 1.05 H), 2.38‒2.57 (m, 2H), 2.97 (s, 1.95 H), 3.02 (s, 1.05 H),
(s, 3H), 3.83 (dd, J = 8.0 and 4.6 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 7.02 3.42‒3.49 (m, 1H), 3.55‒3.65 (m, 1H), 4.08 (br s, 1H), 4.76 (quintet,
(t, J = 7.6 Hz, 1H), 7.20‒7.25 (m, 2H), 8.76 (br s, 1H); 13C NMR J = 6.1 Hz, 0.35 H), 5.53 (q, J = 6.1 Hz, 0.65 H), 6.71 (d, J = 6.9 Hz,
(CDCl3, 125 MHz) δ 34.6, 42.3, 52.0, 109.9, 122.5, 124.1, 128.3, 0.65 H), 6.82 (d, J = 8.4 Hz, 0.35 H), 6.80‒6.95 (m, 2H), 7.08‒7.15
128.7, 141.5, 171.5, 179.1; ESIMS (m/z) 228 [M+Na]+; HRMS (ESI) (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 20.9, 21.0, 30.3, 30.5, 35.5,
calcd for C11H11O3NNa 228.0631, found 228.0627; IR (CHCl3)max 36.1, 45.8, 46.1, 76.5, 79.8, 81.5, 117.3, 118.7, 120.0, 120.9, 123.8,
3427, 1706, 1615 cm-1.
125.2, 125.3, 128.0, 128.1, 141.4, 143.0, 172.8, 174.0; ESIMS (m/z)
255 [M+Na]+; HRMS (ESI) calcd for C13H16O2N2Na 255.1104, found
255.1098; IR (CHCl3)max 3293, 2933, 1684, 1606 cm-1.
Methyl [2-(3-hydroxy-2-oxoindolin-3-yl)ethyl](methyl)carbamate
(3). To a stirred solution of compound 2u (500 mg, 2.01 mmol) in
dry toluene (10 mL) was added t-BuOK (453 mg, 4.03 mmol) at 0 °C 1-Acetyl-2',3'-dimethylspiro[indoline-3,6'-[1,3]oxazinan]-2-one (7).
under oxygen atmosphere. The reaction mixture was stirred at 0 °C To a solution of above mixture of natural product donaxarine (6)
to 25 °C for 4 h and the reaction was quenched by saturated and its precursor 5B (50 mg, 0.216 mmol) in acetic anhydride (4 mL)
aqueous NH4Cl solution (2 mL). The reaction mixture was was added sodium acetate (53 mg, 0.862 mmol) and the reaction
concentrated in vacuo and the obtained residue was dissolved in mixture was stirred at 25 °C for 8 h. The reaction mixture was
ethyl acetate (25 mL). The organic layer was washed with water, concentrated in vacuo and obtained residue was dissolved in ethyl
brine and dried over Na2SO4. The concentration of organic layer in acetate (10 mL) and washed with water, brine and dried over
vacuo followed by silica gel (230400 mesh) column Na2SO4. Concentration of organic layer in vacuo followed by silica
chromatographic purification of the residue by using gel (230400 mesh) column chromatographic purification of the
methanoldichloromethane (0.3:9.7) as an eluent afforded product residue by using ethyl acetatepetroleum ether (3:7) as an eluent
1
3 as a gummy solid (457 mg, 86%). H NMR (DMSO-d6, 400 MHz) afforded product 7 as a white solid (52 mg, 89%). Mp 204–206 °C,
(rotameric mixture) δ 1.95 (s, 2H), 2.70 (s, 3H), 3.17 (s, 2H), 1H NMR (CDCl3, 500 MHz) δ 1.28 (d, J = 6.5 Hz, 3H), 2.25 (s, 3H), 2.40
3.40‒3.60 (m, 3H), 5.98 (s, 1H), 6.81 (d, J = 7.3 Hz, 1H), 6.97 (t, J = (quintet, J = 7.3 Hz, 1H), 2.74 (quintet, J = 6.9 Hz, 1H), 2.88 (s, 3H),
7.3 Hz, 1H), 7.21 (t, J = 7.3 Hz, 1H), 7.28 (d, J = 6.7 Hz, 1H), 10.27 (s, 3.43‒3.50 (m, 1H), 3.57‒3.64 (m, 1H), 6.32 (q, J = 6.5 Hz, 1H),
1H); 13C NMR (DMSO-d6, 100 MHz) δ 33.5, 33.9, 35.0, 35.4, 43.1, 7.17‒7.30 (m, 3H), 7.37 (t, J = 7.6 Hz, 1H); 13C NMR (CDCl3, 125 MHz)
43.5, 52.2, 74.1, 109.7, 121.7, 123.9, 129.1, 131.7, 141.6, 155.7, δ 21.0, 23.1, 30.4, 32.9, 46.0, 77.7, 78.5, 123.6, 125.7, 126.3, 128.5,
178.8; ESIMS (m/z) 287 [M+Na]+; HRMS (ESI) calcd for C13H16O4N2Na 132.3, 136.2, 170.4, 171.4; ESIMS (m/z) 275 [M+H]+; HRMS (ESI)
287.1002, found 287.0996; IR (CHCl3)max 3259, 1716, 1676, 1621 calcd for C15H19O3N2 275.1390, found 275.1389; IR (CHCl3)max 1693,
cm-1.
1662 cm-1.
3-Hydroxy-3-[2-(methylamino)ethyl]indolin-2-one (4). To a 10 mL
sealed tube equipped with a magnetic stirring bar were added
compound 3 (200 mg, 0.76 mmol) and diethylenetriamine (0.33 mL,
3.04 mmol) and the tube was sealed with a Teflon-lined screw cap.
The tube was heated at 120 °C for 6 h. The crude reaction mixture
was directly purified by silica gel (230400 mesh) column
chromatography by using ethyl acetatepetroleum ether (6:4) as an
eluent to afford product 4 as a white solid (160 mg, 91%). Mp 174–
ORCID
Santosh V. Shelar: 0000-0001-9677-3320
Narshinha P. Argade: 0000-0003-4553-4076
Conflicts of interest
There are no conflicts to declare.
1
176 °C, H NMR (CDCl3, 500 MHz) δ 2.43 (td, J = 13.0 and 9.2 Hz,
1H), 2.76 (ddd, J = 12.8, 6.3 and 1.6 Hz, 1H), 2.97 (s, 3H), 3.23‒3.30
(m, 1H), 3.35 (td, J = 9.4 and 1.1 Hz, 1H), 4.40‒4.90 (br s, 2H), 6.70
(t, J = 7.2 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.88 (dd, J = 8.0 and 1.2
Hz, 1H), 7.12 (td, J = 8.2 and 1.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz)
δ 30.2, 32.9, 45.7, 79.4, 118.1, 118.4, 125.2, 125.7, 129.2, 145.8,
175.2; ESIMS (m/z) 207 [M+H]+; HRMS (ESI) calcd for C11H15O2N2
207.1128, found 207.1125; IR (Nujol)max 3350, 1708 cm-1.
Acknowledgements
S. V. S. thanks UGC, New Delhi, for the award of research
fellowship. N. P. A. thanks Science and Engineering Research Board
(SERB), New Delhi for financial support.
Notes and references
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2016, 6, 1‒55. (b) S. R. S. Rudrangi, V. K. Bontha, V. R. Manda and S.
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solution of compound 4 (150 mg, 0.728 mmol) in dichloromethane
(10 mL) was added acetaldehyde (50 µL, 0.788 mmol) at 0 °C under
argon atmosphere. The reaction mixture was stirred at 0 °C to 25 °C
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