Electrocatalytic aldol addition of cyclic 1,3-ketoesters to isatins: Acetone as a solvent for the efficient and facile electrochemically inducedway to 3-substituted-3-hydroxyindol-2-one scaffold

Article abstract of DOI:10.1149/2.021211jes

The electrolysis of isatins and cyclic 1,3-ketoesters in acetone in an undivived cell results in the formation of the previously unknown 3-substituted-3-hydroxyindol-2-ones in 80-95% yields and 800-950% current efficiency. Thus, this simple electrocatalytic system can produce in aprotic solvent in an undivided cell, under mild conditions the new electrochemically induced aldol reaction of isatins and cyclic 1,3-ketoesters with the formation of 3-substituted-3-hydroxyindol-2-ones - promising synthons for different biomedically active compounds. Copyright

Full text of DOI:10.1149/2.021211jes

Journal of The Electrochemical Society, 159 (11) G123-G127 (2012)
G123
0013-4651/2012/159(11)/G123/5/$28.00 © The Electrochemical Society
Electrocatalytic Aldol Addition of Cyclic 1,3-Ketoesters to Isatins:
Acetone as a Solvent for the Efficient and Facile Electrochemically
Induced Way to 3-Substituted-3-Hydroxyindol-2-One Scaffold
M. N. Elinson,a,z V. M. Merkulova,a A. I. Ilovaisky,a A. O. Chizhov,a F. Barba,b
and B. Batanerob
aN. D. Zelinsky Institute of Organic Chemistry, 119991 Moscow, Russia
bDepartment of Organic Chemistry, University of Alcala´, 28871 Alcala´ de Henares, Madrid, Spain
The electrolysis of isatins and cyclic 1,3-ketoesters in acetone in an undivived cell results in the formation of the previously unknown
3-substituted-3-hydroxyindol-2-ones in 80–95% yields and 800–950% current efficiency. Thus, this simple electrocatalytic system
can produce in aprotic solvent in an undivided cell, under mild conditions the new electrochemically induced aldol reaction of isatins
and cyclic 1,3-ketoesters with the formation of 3-substituted-3-hydroxyindol-2-ones – promising synthons for different biomedically
active compounds.
© 2012 The Electrochemical Society. [DOI: 10.1149/2.021211jes] All rights reserved.
Manuscript submitted April 25, 2012; revised manuscript received August 1, 2012. Published August 31, 2012.
The carbon – carbon bond formation is a fundamental process in
organic synthesis and numerous methods have been developed for
achieving it. One of the most powerful methods is the reaction of
the carbonyl groups with a variety of carbon nucleophiles. Thus, the
aldol reaction is very useful carbon-carbon bond forming reaction1,2
of the latter type. In its usual form, it involves the nucleophilic addi-
tion of an aldehyde or a ketone enolate to a carbonyl group to form a
β-hydroxycarbonyl compound, which is called an aldol, a structural
unit occurring in many natural molecules and pharmaceuticals.3–8
In recent years, many research efforts has been invested in the de-
velopment of the direct catalytic aldol reaction, which is generally
considered as one of the most powerful reactions for achieving C–C
bond formation.9
transformation induced by a catalytic amount of an electrogenerated
base in an undivided cell.27
Recently, we have published the electrocatalytic addition of ni-
tromethane and cyclic 1,3-diketones to carbonyl compounds in
methanol solution in an undivided cell.28,29
Considering our preliminary results on the electrocatalytic chain
transformation of aldehydes and CH-acids28–31 as well as the cer-
tain biomedical applications of 3-substituted-3-hydroxyindolin-2-
ones derivatives, we were prompted to design a convenient and
facile electrocatalytic methodology for the efficient synthesis of func-
tionalized 3-substituted-3-hydroxyindolin-2-one scaffold from 1,3-
ketoesters and isatins.
In an aldol condensation and in a Knoevenagel condensation a
nucleophilic addition of an CH-acid anion to a carbonyl group is
followed by a dehydration step.10–13
One of the important examples of aldol type reactions is the Henry
reaction, namely a base-catalyzed reaction between nitroalkanes and
aldehydes or ketones.14,15 The Henry reaction is also a very useful
carbon-carbon bond forming reaction and has wide synthetic applica-
tion in organic synthesis.16
Experimental
All melting points were measured with a Gallenkamp melting point
apparatus and are uncorrected. 1H and 13C NMR spectra were recorded
with a Bruker Avance II-300 at ambient temperature in DMSO-d6 so-
lutions. Chemical shifts values are given in δ scale relative to Me4Si.
IR spectra were registered with a SPECORD M82 spectrometer in
KBr pellets. HRMS (ESI) were measured on a Bruker micrOTOF II
instrument; external or internal calibration was done with Electrospray
Calibrant Solution (Fluka). All starting materials were obtained from
commercial sources and used without purification. Methanol was dis-
tilled over Mg(OMe)2; MeCN and acetone were distilled over P2O5
prior to use. Ethanol with less than 1% of water content was obtained
from commercial sources and used without further purification.
But examples of the aldol reaction of cyclic 1,3-ketoesters with car-
bonyl group yielding aldols (β-hydroxyketoesters) are yet not known
in the literature.
The indole nucleus is a common and important structural function-
ality of a variety of both natural and synthetic products.17 The indole
scaffold represents an important structural subunit for the discovery of
new drug candidates. Many alkaloids and plant hormones contain the
indole ring. The massive search on indole chemistry in recent years
led to a vast number of biologically active compounds with a wide
range of therapeutic targets, such as anti-inflammatory drugs, phos-
phodiesterase inhibitors and HMG-CoA reductase inhibitors and also
to a great number of drugs that contain the indole substructure, such
as indomethacin, ergotamine, frovatriptan, ondansetron, tadalafil.18
Isatin (1H-indole-2,3-dione) and its derivatives have also many
application in medicinal chemistry.19–21 In particular, 3-substituted-3-
hydroxyindolin-2-ones, compounds bearing the indole skeletal struc-
ture, are found in several biologically active alkaloids and pharmaco-
logical agents.22–25
Within the context of green chemistry, electrochemical and espe-
cially electrocatalytic technology can provide a valuable alternative
for the usual chemical synthesis.26 Due to the electron transfer be-
tween an electrode and the substrate the formation of highly reactive
intermediates is achieved under mild conditions, avoiding reductive or
oxidant agents as well as acids, bases and related waste by-products.
In the course of our study on the electrochemical transformation
of organic compounds, we have found a new type of electrochemical
Typical electrolysis procedure.— A mixture of 4-hydroxy-6-
methyl-2H-pyran-2-one 1 or 4-hydroxycoumarin 2 (5 mmol), isatin 3
(5 mmol), and sodium bromide (0.1 g, 1 mmol) in acetone (20 mL)
was electrolyzed in undivided cell equipped with a magnetic stirrer, a
graphite anode and an iron cathode at 20◦C under a constant current
density of 5 mA/cm2 (I = 25 mA, electrodes square 5 cm2) until
the catalytic quantity of 0.1 F mol−1 of electricity was passed. After
the electrolysis was finished, the reaction mixture was concentrated
at 20◦C /10 mm Hg. Water (10 mL) and ether (for 3-substituted-3-
hydroxyindolin-2-ones 4, 10 mL) or chloroform (for 3-substituted-
3-hydroxyindolin-2-ones 5, 10 mL) were added to the residue; the
mixture was stirred for 30 min, the solid product was filtered, washed
with ether or chloroform (2 × 10 mL) and dried at 20◦C/0.1 mm Hg.
3-Hydroxy-3-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-1,3-
dihydro-2H-indol-2-one (4a).— white solid; yield 1.16 g (85%); mp
179–180◦C; δH (300 MHz) 2.16 (s, 3H, CH3), 3.0−4.0 (br s, 1H,
OH), 6.08 (s, 1H, CH), 6.80 (d, J = 7.7, 1H, Ar), 6.91 (t, J = 7.0, 1H,
Ar), 7.16 (d, J = 7.3, 1H, Ar), 7.21 (t, J = 7.7, 1H, Ar), 9.0−11.0 (br
s, 1H, OH), 10.34 (s, 1H, NH); δC (75 MHz) 19.0, 77.5, 98.4, 101.0,
109.6, 121.6, 123.6, 129.6, 131.1, 142.8, 161.7, 162.1, 169.1, 175.7;
zE-mail: elinson@ioc.ac.ru
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G124
Journal of The Electrochemical Society, 159 (11) G123-G127 (2012)
IR (KBr): ν = 3148, 3092, 3036, 1732, 1684, 1584, 1476, 1336, 912,
756; HRMS (ESI) 296.0538 [M+Na]+, calcd for C14H11NO5Na:
296.0529.
3-Hydroxy-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-1,3-dihydro-
2H-indol-2-one (5a).— white solid; yield 1.47 g (95%); mp
188−191◦C; δH (300 MHz) 2.5−4.5 (br s, 1H, OH), 6.85 (d, J = 7.7,
1H, Ar), 6.92 (t, J = 7.3, 1H, Ar), 7.23 (d, J = 7.3, 1H, Ar), 7.25 (d,
J = 7.0, 1H, Ar), 7.37 (d, J = 8.4, 1H, Ar), 7.43 (t, J = 7.7, 1H, Ar),
7.68 (t, J = 7.3, 1H, Ar), 7.93 (d, J = 7.7, 1H, Ar), 9.0–11.0 (br s,
1H, OH), 10.45 (s, 1H, NH); δC (75 MHz) 78.3, 100.9, 109.7, 115.6,
116.1, 121.6, 123.1, 123.8, 124.3, 129.9, 130.7, 132.9, 142.9, 152.2,
159.5, 164.8, 175.4; IR (KBr): ν = 3152, 3096, 3040, 1728, 1672,
1616, 1476, 1340, 1176, 755; HRMS (ESI) 332.0527 [M+Na]+,
calcd for C17H11NO5Na: 332.0529.
3-Hydroxy-3-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-1-
methyl-1,3-dihydro-2H-indol-2-one (4b).— white solid; yield 1.18 g
(82%); mp 140−141◦C; δH (300 MHz) 2.15 (s, 3H, CH3), 3.0−4.0 (br
s, 1H, OH), 3.12 (s, 3H, CH3), 6.08 (s, 1H, CH), 6.92−7.06 (m, 2H,
Ar), 7.22 (d, J = 7.3, 1H, Ar), 7.32 (t, J = 7.3, 1H, Ar), 9.0−11.0 (br
s, 1H, OH); δC (75 MHz) 19.0, 26.1, 77.0, 98.4, 101.1, 108.4, 122.3,
123.2, 129.7, 130.5, 144.1, 161.7, 162.2, 169.1, 174.2; IR (KBr):
ν = 3272, 3124, 1700, 1600, 1584, 1464, 1372, 1216, 900,
752; HRMS (ESI) 310.0684 [M+Na]+, calcd for C15H13NO5Na:
310.0686.
3-Hydroxy-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-1-methyl-1,3-
dihydro-2H-indol-2-one (5b).— white solid; yield 1.47 g (91%); mp
129−133◦C; δH (300 MHz) 2.5−4.5 (br s, 1H, OH), 3.17 (s, 3H,
CH3), 7.00 (t, J = 7.3, 1H, Ar), 7.02 (d, J = 7.7, 1H, Ar), 7.25−7.37
(m, 3H, Ar), 7.40 (t, J = 7.7, 1H, Ar), 7.65 (t, J = 7.7, 1H, Ar), 7.93
(d, J = 7.7, 1H, Ar), 9.0–11.0 (br s, 1H, OH); δC (75 MHz) 26.1,
77.9, 100.3, 108.4, 116.1, 116.3, 122.3, 123.2, 123.3, 124.1, 129.8,
130.6, 132.6, 144.2, 152.3, 159.7, 165.8, 174.3; IR (KBr): ν = 3250,
3110, 1712, 1696, 1628, 1496, 1472, 1340, 1092, 756; HRMS (ESI)
346.0688 [M+Na]+, calcd for C18H13NO5Na: 346.0686.
1-Ethyl-3-hydroxy-3-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-
1,3-dihydro-2H-indol-2-one (4c).— white solid; yield 1.35 g (90%);
mp 116−118◦C; δH (300 MHz) 1.17 (t, J = 7.3, 3H, CH3), 2.14 (s,
3H, CH3), 3.0−4.0 (br s, 1H, OH), 3.57−3.80 (m, 2H, CH2), 6.07 (s,
1H, CH), 6.97 (t, J = 7.3, 1H, Ar), 7.01 (d, J = 7.3, 1H, Ar), 7.22 (d,
J = 7.3, 1H, Ar), 7.30 (t, J = 7.3, 1H, Ar), 9.0−11.0 (br s, 1H, OH);
δC (75 MHz) 11.9, 19.1, 34.1, 76.9, 98.5, 101.1, 108.4, 122.1, 123.4,
129.7, 130.7, 143.2, 161.9, 162.1, 169.0, 173.8; IR (KBr): ν = 3384,
3252, 1712, 1664, 1612, 1584, 1408, 1372, 1200, 760; HRMS (ESI)
324.0841 [M+Na]+, calcd for C16H15NO5Na: 324.0842.
1-Ethyl-3-hydroxy-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-1,3-
dihydro-2H-indol-2-one (5c).— white solid; yield 1.58 g (94%); mp
119−120◦C; δH (300 MHz) 1.21 (t, J = 7.0, 3H, CH3), 2.5−4.5 (br s,
1H, OH), 3.63−3.81 (m, 2H, CH2), 6.99 (t, J = 7.3, 1H, Ar), 7.06 (d,
J = 7.7, 1H, Ar), 7.26−7.39 (m, 3H, Ar), 7.43 (t, J = 7.7, 1H, Ar),
7.68 (t, J = 8.4, 1H, Ar), 7.93 (d, J = 7.7, 1H, Ar), 9.0−11.0 (br s,
1H, OH); δC (75 MHz) 11.9, 34.1, 79.1, 100.9, 108.6, 115.6, 116.1,
122.1, 123.1, 123.6, 124.3, 130.0, 130.2, 132.9, 143.3, 152.2, 159.4,
164.7, 173.5; IR (KBr): ν = 3430, 2976, 1700, 1684, 1632, 1616,
1488, 1376, 1352, 756; HRMS (ESI) 360.0830 [M+Na]+, calcd for
C19H15ClNO5Na: 360.0842.
1-Benzyl-3-hydroxy-3-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-
yl)-1,3-dihydro-2H-indol-2-one (4d).— white solid; yield 1.47 g
(81%); mp 138−139◦C; δH (300 MHz) 2.17 (s, 3H, CH3), 3.0−4.0
(br s, 1H, OH), 4.84 (d, J = 16.1, 1H, CHaHbPh), 4.96 (d, J = 16.1,
1H, CHaHbPh), 6.11 (s, 1H, CH), 6.75 (d, J = 7.7, 1H, Ar), 6.98
(t, J = 7.3, 1H, Ar), 7.15−7.40 (m, 5H, Ar), 7.49 (d, J = 7.3, 2H,
Ar), 9.0–11.0 (br s, 1H, OH); δC (75 MHz) 19.0, 43.0, 77.0, 98.2,
101.2, 109.1, 122.4, 123.4, 127.2, 127.3 (2CH), 128.4 (2CH), 129.6,
130.6, 136.2, 143.3, 161.9, 162.2, 169.3, 174.4; IR (KBr): ν = 3410,
3248, 3060, 1696, 1656, 1616, 1588, 1492, 1220, 760; HRMS (ESI)
386.0981 [M+Na]+, calcd for C21H17NO5Na: 386.0999.
1-Benzyl-3-hydroxy-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-1,3-
dihydro-2H-indol-2-one (5d).— white solid; yield 1.64 g (82%); mp
123–125◦C; δH (300 MHz) 2.5−4.5 (br s, 1H, OH), 4.88 (d, J = 16.1,
1H, CHaHbPh), 4.99 (d, J = 16.1, 1H, CHaHbPh), 6.79 (d, J = 8.1,
1H, Ar), 6.98 (t, J = 7.3, 1H, Ar), 7.19−7.48 (m, 7H, Ar), 7.52 (d, J
= 7.3, 2H, Ar), 7.69 (t, J = 7.3, 1H, Ar), 7.96 (d, J = 7.3, 1H, Ar),
9.0–11.0 (br s, 1H, OH); δC (75 MHz) 43.1, 77.9, 100.6, 109.2, 115.6,
116.2, 122.4, 123.2, 123.6, 124.4, 127.2, 127.3 (2CH), 128.4 (2CH),
129.9, 130.1, 133.0, 136.1, 143.4, 152.2, 159.6, 165.1, 174.2; IR
(KBr): ν = 3300, 3164, 1700, 1616, 1572, 1488, 1172, 760. HRMS
(ESI) 422.0989 [M+Na]+, calcd for C24H17NO5Na: 422.0999.
3-Hydroxy-3-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-5-
methyl-1,3-dihydro-2H-indol-2-one (4e).— white solid; yield 1.19
g (83%); mp 125−127◦C; δH (300 MHz) 2.16 (s, 3H, CH3), 2.21
(s, 3H, CH3), 3.0−4.0 (br s, 1H, OH), 6.08 (s, 1H, CH), 6.69 (d,
J = 7.3, 1H, Ar), 6.98 (s, 1H, Ar), 7.02 (d, J = 7.3, 1H, Ar), 9.0−11.0
(br s, 1H, OH), 10.23 (s, 1H, NH); δC (75 MHz) 19.0, 20.5, 77.6,
98.5, 101.0, 109.3, 124.2, 129.8, 130.41, 131.1, 140.3, 161.6, 162.0,
169.1, 175.6; IR (KBr): ν = 3256, 1712, 1680, 1576, 1496, 1452,
1320, 1220, 1124, 996; HRMS (ESI) 310.0690 [M+Na]+, calcd for
C15H13NO5Na: 310.0686.
3-Hydroxy-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-5-methyl-1,3-
dihydro-2H-indol-2-one (5e).— white solid; yield 1.41 g (87%); mp
>300◦C; δH (300 MHz) 2.19 (s, 3H, CH3), 2.5−4.5 (br s, 1H, OH),
6.74 (d, J = 7.7, 1H, Ar), 7.04 (d, J = 7.7, 1H, Ar), 7.06 (s, 1H, Ar),
7.36 (d, J = 8.4, 1H, Ar), 7.42 (t, J = 7.7, 1H, Ar), 7.67 (t, J = 7.3,
1H, Ar), 7.92 (d, J = 7.7, 1H, Ar), 9.0−11.0 (br s, 1H, OH), 10.34
(s, 1H, NH); δC (75 MHz) 20.4, 78.4, 100.9, 109.5, 115.70, 116.1,
123.1, 124.3, 124.4, 130.0, 130.6, 130.8, 132.8, 140.5, 152.2, 159.5,
164.8, 175.5; IR (KBr): ν = 3360, 3024, 1716, 1672, 1628, 1576,
1492, 1344, 964, 760; HRMS (ESI) 346.0687 [M+Na]+, calcd for
C18H13NO5Na: 346.0686.
5-Chloro-3-hydroxy-3-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-
yl)-1,3-dihydro-2H-indol-2-one (4f).— white solid; yield 1.31 g
(85%); mp 139−141◦C; δH (300 MHz) 2.15 (s, 3H, CH3), 3.0−4.0
(br s, 1H, OH), 6.07 (s, 1H, CH), 6.81 (d, J = 8.0, 1H, Ar), 7.18 (s,
1H, Ar), 7.26 (d, J = 7.3, 1H, Ar), 9.0−11.0 (br s, 1H, OH), 10.46 (s,
1H, NH); δC (75 MHz) 19.0, 77.3, 97.8, 101.2, 111.0, 123.7, 125.4,
129.3, 133.2, 141.7, 161.9, 162.2, 169.4, 175.6; IR (KBr): ν = 3256,
1716, 1684, 1576, 1480, 1448, 1320, 1224, 1184, 812; HRMS (ESI)
330.0140 [M+Na]+, calcd for C14H10ClNO5Na: 330.0140.
5-Chloro-3-hydroxy-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-1,3-
dihydro-2H-indol-2-one (5f).— white solid; yield 1.46 g (85%); mp
>300◦C; δH (300 MHz) 2.5−4.5 (br s, 1H, OH), 6.86 (d, J = 8.1,
1H, Ar), 7.20−7.48 (m, 4H, Ar), 7.67 (t, J = 7.3, 1H, Ar), 7.92 (d, J
= 7.3, 1H, Ar), 9.0−11.0 (br s, 1H, OH), 10.59 (s, 1H, NH); δC (75
MHz) 78.2, 100.2, 111.2, 115.7, 116.2, 123.2, 124.1, 124.3, 125.6,
129.6, 132.8, 132.9, 141.8, 152.3, 159.7, 165.2, 175.4; IR (KBr):
ν = 3408, 3208, 1724, 1672, 1620, 1576, 1480, 1308, 960, 756;
HRMS (ESI) 366.0129 [M+Na]+, calcd for C17H10ClNO5Na:
366.0140.
5-Bromo-3-hydroxy-3-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-
yl)-1,3-dihydro-2H-indol-2-one (4g).— white solid; yield 1.40 g
(80%); mp 143−146◦C; δH (300 MHz) 2.15 (s, 3H, CH3), 3.0−4.0
(br s, 1H, OH), 6.05 (s, 1H, CH), 6.76 (d, J = 8.0, 1H, Ar), 7.28 (s,
1H, Ar), 7.38 (d, J = 7.3, 1H, Ar), 9.0−11.0 (br s, 1H, OH), 10.45 (s,
1H, NH); δC (75 MHz) 19.0, 77.2, 97.6, 101.3, 111.5, 112.9, 126.3,
132.1, 133.7, 142.1, 161.9, 162.1, 169.6, 175.5; IR (KBr): ν = 3392,
3250, 1728, 1680, 1580, 1476, 1448, 1320, 1224, 1180; HRMS (ESI)
373.9626 [M+Na]+, calcd for C14H10BrNO5Na: 373.9635.
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Journal of The Electrochemical Society, 159 (11) G123-G127 (2012)
G125
O
O
OH
R2
HO
HO
electrolysis, 0.1 F/mol, 20 oC
+
R2
O
O
NaBr, acetone
N
R1
O
O
O
N
R1
3a-g
1
4a-g
OH
O
O
R2
HO
HO
electrolysis, 0.1 F/mol, 20 oC
R2
O
O
+
NaBr, acetone
N
R1
O
O
O
N
R1
2
3a-g
5a-g
a R1 = R2 = H; b R1 = Me, R2 = H;c R1 = Et, R2 = H; d R1 = CH2Ph, R2 = H;
e R1 = H, R2 = Me; f R1 = H, R2 = Cl;g R1 = H, R2 = Br
Scheme 1. Electrochemically induced addition of cyclic 1,3-ketoesters 1,2 to isatins 3a–g.
5-Bromo-3-hydroxy-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-1,3-
dihydro-2H-indol-2-one (5g).— white solid; yield 1.55 g (80%); mp
>300◦C; δH (300 MHz) 2.5−4.5 (br s, 1H, OH), 6.71 (d, J = 8.1,
1H, Ar), 7.16−7.34 (m, 4H, Ar), 7.52 (t, J = 8.1, 1H, Ar), 7.86 (d, J
= 8.1, 1H, Ar), 9.0−11.0 (br s, 1H, OH), 10.17 (s, 1H, NH); δC (75
MHz) 78.2, 100.1, 111.7, 113.2, 115.8, 116.2, 123.2, 124.3, 126.7,
132.4, 132.9, 133.2, 142.3, 152.3, 159.7, 165.2, 175.2; IR (KBr):
ν = 3200, 1732, 1672, 1620, 1560, 1476, 1304, 956, 816, 756; HRMS
(ESI) 409.9628 [M+Na]+, calcd for C17H10BrNO5Na: 409.9635.
cell was studied (Table I). Data in Table I show that 3-substituted-3-
hydroxyindol-2-one 4a in methanol is formed only in moderate (50%)
yield under conditions studied. An increase yield of 4a was found
when the electrolysis was carried out in aprotic solvents: acetonitrile
(76%) and especially acetone (88%). This fact could be explained
by the influence of two factors: 1) the direct reduction of 4-hydroxy-
6-methyl-2H-pyran-2-one 1 at the cathode in aprotic solvent; 2) the
increase of CH-acidity of ketoesters in aprotic solvents compare with
their acidity in alcohols.32 A similar tendency was also found for
the addition of 4-hydroxycoumarin 2 to isatin 3a. In the latter case
the yield of 3-substituted-3-hydroxyindol-2-one 5a in acetone is also
higher than in alcohols (95% and 70% respectively). Under the opti-
Results and Discussion
In the present study, we report our results on the electrochemically
induced addition of cyclic 1,3-ketoesters 1,2 to isatins 3a–g in an
undivided cell (Scheme 1, Tables I and II).
First, to evaluate the synthetic potential of the procedure pro-
posed and to optimize the electrolysis conditions, the electrocat-
alytic addition of 4-hydroxy-6-methyl-2H-pyran-2-one 1 and 4-
hydroxycoumarin 2 to isatin 3a in alcohol solution in an undivided
mal conditions thus found (I = 25 mA, current density 5 mA cm−2
,
0.1 F mol−1 passed, time 32 min, acetone as a solvent) the electroly-
sis of 4-hydroxy-6-methyl-2H-pyran-2-one 1 and 4-hydroxycoumarin
2 with isatins 3a–g in acetone in an undivided cell resulted in the
formation of the corresponding 3-substituted-3-hydroxyindol-2-ones
4a–g and 5a–g in 80–95% yields and 800–950% current efficiency
(Table II).
Table I. Electrocatalytic addition of ketoesters 1 and 2 to isatin 3a with the formation of aldol adducts 4a and 5aa.
Entry
Ketoester
Solvent
Current density (mA cm−2
)
Time (min)
Electricity passed (F mol−1
)
Product, yield (%)b
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
2
2
2
MeOH
EtOH
EtOH
5
5
5
10
5
5
5
5
5
5
32
32
48
16
32
32
48
32
32
32
0.10
0.10
0.15
0.10
0.10
0.10
0.15
0.10
0.10
0.10
4a, 50 (500)
4a, 49 (490)
4a, 51 (340)
4a, 48 (480)
4a, 76 (760)
4a, 85 (850)
4a, 88 (587)
5a, 71 (710)
5a, 75 (750)
5a, 95 (950)
EtOH
MeCN
Me2CO
Me2CO
MeOH
EtOH
10
Me2CO
aKetoester 1 or 2 (5 mmol), isatin 3a (5 mmol), NaBr (1 mmol), solvent (20 mL), iron cathode (5 cm2), graphite anode (5 cm2), 20◦C.
bYield of isolated product (in parentheses, current efficiency is given).
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G126
Journal of The Electrochemical Society, 159 (11) G123-G127 (2012)
Table II. Electrocatalytic addition of ketoesters 1,2 to isatins 3a–g with the formation of aldol adducts 4a–g and 5a–ga.
Ketoester
Isatin
I (mA)
Current density (mA cm−2
)
Time (min)
Electricity passed (F mol−1
)
Product
Yield (%)b
1
1
1
1
1
1
1
2
2
2
2
2
2
2
3a
3b
3c
3d
3e
3f
3g
3a
3b
3c
3d
3e
3f
25
25
25
25
25
25
25
25
25
25
25
25
25
25
5
5
5
5
5
5
5
5
5
5
5
5
5
5
32
32
32
32
32
32
32
32
32
32
32
32
32
32
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
4a
4b
4c
4d
4e
4f
4g
5a
5b
5c
5d
5e
5f
85 (850)
82 (820)
90 (900)
81 (810)
83 (830)
85 (850)
80 (800)
95 (950)
91 (910)
94 (940)
82 (820)
87 (870)
85 (850)
80 (800)
3g
5g
aKetoester 1 or 2 (5 mmol), isatin 3 (5 mmol), NaBr (1 mmol), acetone (20 mL), iron cathode (5 cm2), graphite anode (5 cm2), 20◦C.
bYield of isolated product (in parentheses, current yield is given).
Taking into consideration the above data and our previous
results28–31 the following mechanism for the electrochemically in-
duced aldol reaction of cyclic 1,3-ketoesters 1,2 with isatins 3a–g in
acetone is proposed (Scheme 2, example with the cyclic ketoester 2).
The initiation step is the reduction of the O-H bond of the enol
of the cyclic 1,3-ketoester, which leads to the formation of the cyclic
1,3-ketoester anion A. The evolution of hydrogen at the cathode is
observed, especially when electrolysis is conducted without stirring
of the reaction mixture.
Then the propagation step takes place, namely the addition of the
cyclic 1,3-ketoester anion to isatin with the formation of the interme-
diate anion B. The chain transfer step is the subsequent reaction of
anion B with another molecule of the ketoester 3 with the formation
of the final product of the electrocatalytic process, i.e. the correspond-
ing 2-(3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)cyclohexane-1,3-
dione 5 and the regeneration of new anion A. Then anion A continues
the catalytic chain process by the interaction with the next molecule
of isatin. (Scheme 2).
Conclusions
In conclusion, the simple electrocatalytic system described can
produce, under mild conditions in an undivided cell, and in an aprotic
solvent such as acetone, a fast and selective previously unknown aldol
reaction of cyclic 1,3-ketoesters with isatins to form substituted 3-
hydroxy-3-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-1,3-dihydro-
2H-indol-2-ones or 3-hydroxy-3-(4-hydroxy-2-oxo-2H-chromen-3-
yl)-1,3-dihydro-2H-indol-2-ones in 80–95% yields and 800–950%
current efficiency. This electrocatalytic chain process is an efficient
and convenient access to substituted 3-hydroxy-3-(4-hydroxy-6-
methyl-2-oxo-2H-pyran-3-yl)-1,3-dihydro-2H-indol-2-ones
and
O
OH
+ 1/2 H2
+e
initiation
O
O
O
O
A
2
O
O
O
HO
R2
propagation
O
R2
O
O
+
N
R1
O
O
O
N
R1
3
A
B
O
O
HO
HO
OH
O
O
R2
O
HO
R2
O
+
+
O
chain transfer
O
N
R1
O
O
N
R1
O
O
A
B
2
5
Scheme 2. Mechanism of electrochemically induced addition of cyclic 1,3-ketoesters 1,2 to isatins 3a–g.
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Journal of The Electrochemical Society, 159 (11) G123-G127 (2012)
G127
3-hydroxy-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-1,3-dihydro-2H-
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Acknowledgments
The authors gratefully acknowledge the financial support of the
Russian Foundation for Basic Research (Project No. 09-03-00003).
The authors also thank the Department of Structural Studies of Zelin-
sky Institute of Organic Chemistry, Moscow for providing high reso-
lution mass spectra.
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