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DOI: 10.1055/s-0040-1707816
Krapcho Dealkoxycarbonylation Strategy of Ethyl Cyanoacetate for the Synthesis of 3-Hydroxy-3-cyanomethyl-2-oxindoles and 3,3′-Dicyanomethyl-2-oxindoles in a Reaction with Isatin
Publication History
Received: 22 December 2019
Accepted after revision: 30 April 2020
Publication Date:
25 May 2020 (online)
Abstract
A new strategy for the synthesis of 3-hydroxy-3-cyanomethyl-2-oxindoles and 3,3′-dicyanomethyl-2-oxindoles in a reaction of isatin with ethyl cyanoacetate by Krapcho dealkoxycarbonylation reaction in aqueous media is demonstrated. The reaction provides an easy access to synthetically and medicinally valuable oxindole alkylnitriles in good to very good yields. Wider substrate scope and operationally simple experimental procedures are highlighted features of the developed protocol. Based on control experiments, a plausible mechanism of reaction and synergistic effect of water is also rationalized.
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Key words
aldol-type cyanomethylation - dealkoxycarbonylation - 3,3′-disubstituted oxindole - ethyl cyanoacetate - isatinThe successful application of a synthetic methodology heavily relies on the reaction solvent being used preferably due to their ability to facilitate the transformation. Given consideration to environmental concern, the use of water as a reaction medium is given priority over traditional organic solvents preferably due to mild reaction conditions and nontoxic behavior.[1] Water, like bioethanol and glycerol, has been the center of interest for developing as reaction medium for synthetic manipulation due to its unique physicochemical characteristics.[2] Numerous metal-catalyzed reactions have recently been demonstrated to undergo specific and selective functional group transformations utilizing water as the reaction medium.[3] Krapcho dealkoxycarbonylation reaction of methyl or ethyl esters bearing electron-withdrawing groups at α-position provides an opportunity to access useful substrate with demonstrated applications in organic transformations and total synthesis of natural products.[4] Recently, this protocol has been utilized in the process development of antiulcer and ophthalmic drug Rebamipide.[5]
The creation of natural products like heterocyclic scaffolds of pharmaceutical interests has garnered interest due to its potential applications in medicinal chemistry.[6] The ability to act selectively on biological targets has paved their way as a valuable treasure in the drug discovery program.[7] Particularly, the oxindole derivatives are ubiquitous in natural products and essentially mark their presence in the realm of natural product guided development of novel drug candidates.[8] Among oxindole class of molecules, the 3-hydroxy-2-oxindole derivatives have been the center of attraction not only because of their pharmacological activities but also for their ease of functionalization leading to diverse natural products and pharmaceutical agents.[9] Their synthetic potentials have been best demonstrated in formal and total syntheses of many bioactive natural products such as (±)-alline, (±)-CPC-1, and (±)-flustraminol B (Figure [1]).[10]
Alkyl nitriles are the quintessential class of synthetic intermediates widely explored in the synthesis of several natural products and bioactive molecules.[11] Their easy conversion into aldehyde, amine, or carboxylic acid derivatives underscore the value of alkyl nitriles as important synthetic precursors. Consequently, a great deal of attention has been paid towards the development of synthetic methods leading to β-hydroxy nitriles including metal-mediated reactions.[12]
The most common methods employed for oxindole-based alkyl nitriles include base-catalyzed deprotonation of acetonitrile followed by nucleophilic addition to isatin. For example, palladium-catalyzed C–H activation of acetonitrile followed by addition to isatin via aldol type cyanoalkylation,[13] catalytic decarboxylative [1,2] addition of α-functionalized acetic acids onto isatin,[14] DBU-mediated diastereoselective aldol-type cyanomethylation of isatins,[15] and recently appeared organocatalytic cyanoarylmethylation of isatin with phenyl acetonitrile[16] are some of the well-documented synthetic protocols for oxindole based alkyl nitriles (Scheme [1]).
To the best of our knowledge, only two synthetic protocols for the synthesis of 3,3′-dicyanomethyl-2-oxindoles have been documented until now (Scheme [2]).[17] As a part of our research program directed towards the development of synthetic methods involving isatin in aqueous solvents,[18] herein we report a new strategy for the synthesis of 3-hydroxy-3-cyanomethyl-2-oxindoles and 3,3′-dicyanomethyl-2-oxindoles via Krapcho dealkoxycarbonylation reaction of ethyl cyanoacetate with isatin.
a Reaction conditions: 1a (1.36 mmol), 2a (1.36 mmol), base (1.36 mmol), additive (1.36 mmol).
b Isolated yield after chromatographic purification.
We began our investigation by performing a reaction of isatin (1a) with an equimolar ratio of ethyl cyanoacetate (2a) in water at 80 °C with DBU as a base to test our initial hypothesis. The expected β-hydroxy nitrile 3a was obtained in 45% yield as the initial experimental outcome after 15 hours of reaction (Table [1], entry 1). To enhance the yield, we turned our attention towards optimization of reaction conditions. First, the role of base was evaluated using several organic and inorganic bases like DBU, DMAP, DABCO, Et3N, K2CO3, KOH, and NaOH. Amongst attempted organic bases (entries 1–6), DABCO was found to be the most suitable base with 70% yield of 3a (entry 2) whereas a least yield of only 25% was obtained with pyridine (entry 3). With inorganic bases (entries 7–10), the monocyanomethylation was found to be sluggish with poor yield ranging 20–27% only. The effect of solvent on the course of reaction was observed crucial as 3a was only isolated in aqueous media (entries 11–19). The reaction in water only furnished a maximum yield of 70% (entry 2) whereas the use of 1:1 mixture of water/hexane and water/petroleum ether was effective and provided 3a in 64% and 68% yield, respectively (entries 11, 12). The reaction in other solvents like MeCN, DCE, THF, toluene, etc. failed to provide 3a (entries 13–19).
As the reaction proceeds via Krapcho dealkoxycarbonylation where metal salt plays a crucial role, the effect of salt as additive on the reaction was investigated. The reaction was performed with several salts like NaCl, KCl, and NH4Cl (Table [1], entries 20–22) but only NaCl was found effective in only reducing the reaction time from 12 to 8 hours. However, it failed to provide any enhancement in the yield of 3a (entry 20).The other salts like KCl and NH4Cl were not very effective for monocyanomethylation as even after 24 hours of reaction only moderate yield of 3a was obtained (entries 21, 22). Since this alkylation reaction proceeded without addition of any additive, no salt was used for the reaction.
Next, the substrate scope for the reaction was evaluated after achieving the optimized reaction conditions. Both electron-donating and electron-withdrawing substituents on isatin provided a good yield of monocyanomethylation (Scheme [3]). The electron-donating (5-Me and 5-OMe) and electron-withdrawing 5-F, 5-Cl, and 5-Br) groups on the oxindole were found tolerable to afford the expected 3-substituted-3-hydroxyoxindole derivatives in good to very good yields (Scheme [3]). The iodo and nitro derivatives showed poor reactivity towards dealkoxycarbonylative cyanomethylation as only traces of the desired product were observed. The substitution at 7-position, 4,7-, and 5,7-positions on isatin were also found compatible with reaction conditions. The free as well as N-alkylated isatins both were also well tolerated with optimized conditions and furnished the expected product in high yields.
During the investigation of optimized reaction conditions in a reaction of isatin (1a) and ethyl cyanoacetate (2a), we did notice the formation of trace amount of 4a on TLC, which was characterized as 3,3′-dicyanomethyloxindole derivative. Interestingly, the formation of 4a was observed more intense with increasing molar ratio of 2a, which was formed by double dealkoxycarbonylation process. The formation of 4a prompted us to investigate the reaction with an increased molar ratio of ethyl cyanoacetate. We performed a reaction of isatin (1a) with two equivalent of ethyl cyanoacetate (2a) using water as a reaction medium and DABCO as a base at 80 °C. To our delight, we were able to isolate 4a in 65% yield with only traces amount of 3a.
a Reaction conditions: 1a (1.36 mmol), 2a (2.72 mmol), DABCO (1.36 mmol).
b Isolated yield after chromatographic purification.
Like 3a, the formation of 4a was only observed in water using DABCO as a base in 65% yield (Table [2], entry 1). The use of 1:1 mixture of H2O/hexane and H2O/petroleum ether also yielded product 4a in 55% yield (entries 2, 3). Expectedly, no product formation was observed in organic solvents like MeCN, DCE, THF, and toluene (entries 6–10). Henceforth it was also observed that water is found to be essential for dicyanomethylation of isatin. For the substrate scope with optimized conditions, both electron-donating (5-Me and 5-OMe) and electron-withdrawing (5-F, 5-Cl, and 5-Br) groups on the oxindole ring were tolerable to afford the desired 3,3-disubstituted oxindole derivatives in good to very good yields (Scheme [4]). To our surprise, no product was observed with iodo- and nitroisatin derivatives.
To provide understanding about the mechanistic pathway of reaction, a few control experiments were planned and executed. Thus, isatin (1a) was allowed to react with ethyl cyanoacetate (2a) in water with DABCO at room temperature for 6 hours to provide the red solid 5a in 80% yield.[18d] Compound 5a on further treatment with ethyl cyanoaceatate (2a) under similar conditions provided 4a in 60% of yield. To see the effect of dealkoxycarbonylation of ester, 5-bromoisatin (1c) was treated with diethyl malonate (2b), which provided only monoalkylated product 6c in 60% yield without any dialkylated product (Scheme [5]). Compound 5a was also subjected to heating conditions with DABCO to observe the dealkoxy carbonyl group, but no product was observed.
Based on product structure and outcome of control experiments, a plausible mechanism for product formation is depicted in Scheme [6]. Ethyl cyanoacetate (2a) undergoes aldol-type nucleophilic addition to isatin (1a) to provide β-hydroxy nitrile derivative A, which subsequently undergoes Krapcho dealkoxycarbonylation leading to product 3a. With an excess of 2a, Knoevenagel condensation of isatin leads to the formation of 5a which consequently undergoes conjugate addition with another molecule of 2a leading to B, which subsequently on double Krapcho dealkoxycarbonylation yields 4a.
The synergistic effect of water in several synthetic transformations has already been investigated[19] and based on our product outcome and literature precedents, a possible transition state highlighting the role of water in the reaction is shown in Figure [2]. The hydrogen bonding with water is the driving force to felicitate deprotonation of ethyl cyanoacetate (2a), which leads to a nucleophilic attack on the carbonyl group of isatin (1a). Due to hydrogen bonding with water, reactive sites orient themselves on the periphery of the hydrophilic part of the phase boundary.
In conclusion, we have developed an attractive and metal-free approach for aldol type cyanomethylation and dicyanomethylation of isatin with ethyl cyanoacetate by Krapcho dealkoxycarbonylation reaction strategy. The developed protocol is environmentally benign and yields a distinct class of synthetically and pharmaceutically useful 3-hydroxy-3-cyanomethyl-2-oxindole and 3,3′-dicyanomethyl-2-oxindole derivatives. A plausible mechanism for product formation was rationalized based on control experiments. The Krapcho dealkoxycarbonylation strategy was demonstrated to be effective even in the absence of metal salt.
All the chemicals and reagents isatin, ethyl cyanoacetate, diethyl malonate, and DABCO were purchased from Sigma-Aldrich or Spectrochem. All the reactions were performed in open air and the progress of reaction was monitored by use of TLC. The NMR spectra were recorded in DMSO-d 6 at 400 MHz for 1H and 100 MHz for 13C on Bruker Avance DPX-400 MHz spectrometer. Chemical shifts are reported in δ (ppm) relative to DMSO-d 6 as internal standard. Integrals are in accordance with assignments, coupling constants are given in hertz (Hz). The HRMS data were recorded on a JOEL AccuTOF JMS-T100LC mass spectrometer having a DART source. The yields refer to quantities obtained after column chromatography. Melting points were recorded by using LABINDIA and are uncorrected.
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2-(3-Hydroxy-2-oxoindolin-3-yl)acetonitrile (3a)[14]; Typical Procedure
To a stirred mixture of isatin (1a; 200 mg, 1.36 mmol) in H2O (10 mL) were added ethyl cyanoacetate (2a; 0.145 mL, 1.36 mmol) and DABCO (152 mg, 1.36 mmol) and the reaction mixture was allowed to stir vigorously at 80 °C for 12 h. After TLC had indicated complete consumption of the starting material, the reaction mixture was extracted with EtOAc (3 ×), and the combined organic layers were dried (Na2SO4) and evaporated. The crude reaction mixture was purified by column chromatography using EtOAc/hexane (4:6) as an eluent to afford to afford 3a as a white solid; yield: 178 mg (70%); mp 177–179 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.51 (s, 1 H), 7.35–7.51 (m, 1 H), 7.18–7.31 (m, 1 H), 6.93–7.07 (m, 1 H), 6.73–6.89 (m, 1 H), 6.56 (s, 1 H), 3.30 (d, J = 16 Hz, 1 H), 2.91 (d, J = 12 Hz, 1 H).
13C NMR (100 MHz, DMSO-d 6): δ = 176.6, 141.5, 129.9, 129.7, 124.1, 121.9, 117.0, 110.0, 71.9, 26.1.
HRMS: m/z calcd for C10H8N2O2 [M + H]+: 189.0664; found: 189.0657.
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2-(5-Chloro-3-hydroxy-2-oxoindolin-3-yl)acetonitrile (3b)[14]
Grey solid; yield: 154 mg (63%); mp 185–187 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.69 (s, 1 H), 7.49–7.49 (m, 1 H), 7. 34–7.37 (m, 1 H), 6.89 (d, J = 8.31 Hz, 1 H), 6.75 (s, 1 H), 3.03 (d, J = 16 Hz, 1 H), 3.11 (d, J = 16 Hz, 1 H).
13C NMR (100 MHz, DMSO-d 6): δ = 176.7, 141.0, 132.1, 130.2, 126.4, 124.8, 117.3, 112.0, 72.5, 26.2.
HRMS: m/z calcd for C10H7ClN2O2 [M + H]+: 223.0274; found: 223.0299.
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Bromo-3-hydroxy-2-oxoindolin-3-yl)acetonitrile (3c)[14]
Grey solid; yield: 120 mg (51%); mp 165–167 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.69 (s, 1 H), 7.61–7.61 (m, 1 H), 7.48 (m, 1 H), 6.84 (d, J = 8.0 Hz, 1 H), 6.75 (s, 1 H), 3.12 (d, J = 16 Hz, 1 H), 3.03 (d, J = 16 Hz, 1 H).
13C NMR (100 MHz, DMSO-d 6): δ = 176.6, 141.4, 133.1, 132.5, 127.5, 117.3, 114.0, 112.5, 72.5, 26.2.
HRMS: m/z calcd for C10H7BrN2O2 [M + 2 H]+: 267.9847; found: 267.9811.
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2-(5-Fluoro-3-hydroxy-2-oxoindolin-3-yl)acetonitrile (3d)[14]
Grey solid; yield: 124 mg (50%); mp 192–194 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.58 (s, 1 H), 7.30 (dd, J = 8.0 Hz, 1 H), 7.11–7.17 (m, 1 H), 6.87 (dd, J = 8.0 Hz, 1 H), 6.74 (s, 1 H), 3.10 (d, J = 16 Hz, 1 H), 3.02 (d, J = 16 Hz, 1 H).
13C NMR (100 MHz, DMSO-d 6): δ = 177.0, 138.2, 131.8, 117.3, 116.8, 116.6, 116.5, 112.5, 112.2, 111.5, 111.4, 72.7. 26.3.
HRMS: m/z calcd for C10H7FN2O2 [M + H]+: 207.0570; found: 207.0571.
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2-(3-Hydroxy-5-methyl-2-oxoindolin-3-yl)acetonitrile (3e)[14]
White solid; yield: 140 mg (56%); mp 175–177 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.43 (br s, 1 H), 7.28 (s, 1 H), 7.10 (br d, J = 7.58 Hz, 1 H), 6.76 (br d, J = 7.82 Hz, 1 H), 6.55 (s, 1 H), 3.03 (br d, J = 16.63 Hz, 1 H), 2.93 (br d, J = 16.0 Hz, 1 H), 2.28 (s, 3 H).
13C NMR (100 MHz, DMSO-d 6): δ = 177.1, 139.5, 131.3, 130.6, 130.3, 125.1, 117.5, 110.2, 72.5, 26.6, 21.1.
HRMS: m/z calcd for C11H10N2O2 [M + H]+: 203.0821; found: 203.0822.
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2-(3-Hydroxy-5-methoxy-2-oxoindolin-3-yl)acetonitrile (3f)[14]
White solid; yield: 177 mg (72%); mp 171–173 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.37 (s, 1 H), 7.10 (d, J = 2.57 Hz, 1 H), 6.88–6.85 (m, 1 H), 6.79 (d, J = 8.0 Hz, 1 H), 6.61 (s, 1 H), 3.73 (s, 3 H), 3.06 (d, J = 16 Hz, 1 H), 2.95 (d, J = 20 Hz, 1 H).
13C NMR (100 MHz, DMSO-d 6): δ = 177.0, 155.5, 135.1, 131.3, 117.4, 115.0, 111.6, 110.9, 72.8, 56.0, 26.5.
HRMS: m/z calcd for C11H10N2O3 [M + H]+: 219.0770; found: 219.0763.
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2-(7-Bromo-3-hydroxy-2-oxoindolin-3-yl)acetonitrile (3g)
Grey solid; yield: 123 mg (52%); mp 168–170 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.87 (s, 1 H), 7.46–7.51 (m, 2 H), 7.0–7.04 (m, 1 H), 7.0–7.04 (m, 1 H), 3.09 (d, J = 16.0 Hz, 1 H), 3.04 (d, J = 16.0 Hz, 1 H).
13C NMR (100 MHz, DMSO-d 6): δ = 177.0, 141.4, 133.2, 124.25, 123.6, 117.3, 102.9, 73.2, 26.4.
HRMS: m/z calcd for C10H7BrN2O2 [M + 2 H]+: 267.9847; found: 267.9782.
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2-(7-Fluoro-3-hydroxy-2-oxoindolin-3-yl)acetonitrile (3h)[20]
Grey solid; yield: 147 mg (59%); mp 157–159 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 11.08 (br s, 1 H), 7.32 (d, J = 8 Hz, 1 H), 7.23 (t, J = 16 Hz, 1 H), 7.05–7.12 (m, 1 H), 6.75 (s, 1 H), 3.33 (d, J = 16 Hz, 1 H), 3.02 (d, J = 16 Hz, 1 H).
13C NMR (100 MHz, DMSO-d 6): δ = 176.9, 123.2, 120.6, 117.5, 117.4, 117.3, 72.5, 39.9, 26.4.
HRMS: m/z calcd for C10H7FN2O2 [M + H]+: 207.0570; found: 207.0571.
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2-(4,7-Dichloro-3-hydroxy-2-oxoindolin-3-yl)acetonitrile (3i)
White solid; yield: 159 mg (67%); mp 183–185 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 11.30 (br s, 1 H), 7.43 (d, J = 8.0 Hz, 1 H), 7.09 (d, J = 8.68 Hz, 1 H), 6.91 (s, 1 H), 3.34 (br d, J = 16.0 Hz, 1 H), 3.20 (br d, J = 16.0 Hz, 1 H).
13C NMR (100 MHz, DMSO-d 6): δ = 176.2, 141.9, 132.07, 129.3, 127.4, 124.5, 116.3, 113.8, 74.5, 23.9.
HRMS: m/z calcd for C10H6Cl2N2O2 [M + H]+: 256.9885; found: 256.9886.
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2-(5,7-Dichloro-3-hydroxy-2-oxoindolin-3-yl)acetonitrile (3j)[21]
White solid; yield: 138 mg (58%); mp 187–189 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 11.19 (s, 1 H), 7.57 (d, J = 1.96 Hz, 1 H), 7.48 (d, J = 1.96 Hz, 1 H), 6.90 (s, 1 H), 3.15 (d, J = 16.0 Hz, 1 H), 3.06 (d, J = 16.0 Hz, 1 H).
13C NMR (100 MHz, DMSO-d 6): δ = 176.7, 139.0, 133.4, 129.7, 127.0, 123.6, 117.1, 115.4, 73.1, 26.0.
HRMS: m/z calcd for C10H6Cl2N2O2 [M + H]+: 256.9885; found: 256.9882.
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2-(5,7-Dibromo-3-hydroxy-2-oxoindolin-3-yl)acetonitrile (3k)[14]
White solid; yield: 143 mg (63%); mp 195–197 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 11.06 (s, 1 H), 7.77 (s, 1 H), 7.62 (s, 1 H), 6.88 (s, 1 H), 3.15 (br d, J = 16.0 Hz, 1 H), 3.10 (br d, J = 16.0 Hz, 1 H).
13C NMR (100 MHz, DMSO-d 6): δ = 176.5, 141.1, 135.0, 133.8, 126.7, 117.1, 114.5, 103.8, 73.2, 26.0.
HRMS: m/z calcd for C10H6Br2N2O2 [M + 4 H]+: 347.9109; found: 347.8870.
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2-(3-Hydroxy-1-methyl-2-oxoindolin-3-yl)acetonitrile (3l)[14]
White solid; yield: 153 mg (61%); mp 180–182 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 7.52 (d, J = 8.0 Hz, 1 H), 7.41 (t, J = 8.0 Hz, 1 H), 7.13 (t, J = 8.0 Hz, 1 H), 7.07 (d, J = 8.0 Hz, 1 H), 6.67 (s, 1 H), 3.14 (s, 3 H), 6.67 (s, 1 H), 3.08 (br d, J = 16.0 Hz, 1 H), 2.99 (br d, J = 16.0 Hz, 1 H).
13C NMR (100 MHz, DMSO-d 6): δ = 175.4, 143.5, 130.6, 129.6, 124.1, 123.1, 117.4, 109.4, 72.2, 26.6 26.5.
HRMS: m/z calcd for C11H10N2O2 [M + H]+: 203.0821; found: 203.0816.
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2-(5-Chloro-3-hydroxy-1-methyl-2-oxoindolin-3-yl)acetonitrile (3m)[22]
White solid; yield: 128 mg (53%); mp 167–169 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 7.54 (d, J = 8.0 Hz, 1 H), 7.47 (dd, J = 8.0 Hz, 1 H), 7.12 (d, J = 8.0 Hz, 1 H), 6.82 (s, 1 H), 3.14 (s, 3 H), 3.14 (br d, J = 16.0 Hz, 1 H), 3.07 (br d, J = 16.0 Hz, 1 H).
13C NMR (100 MHz, DMSO-d 6): δ = 175.0, 142.4, 131.5, 130.3, 127.1, 124.4, 117.2, 111.0, 72.2, 26.6, 26.2.
HRMS: m/z calcd for C11H9ClN2O2 [M + H]+: 237.0431; found: 237.0432.
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2-(5-Bromo-3-hydroxy-1-methyl-2-oxoindolin-3yl)acetonitrile (3n)[22]
White solid; yield: 126 mg (54%); mp 175–177 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 7.65 (d, J = 4.0 Hz, 1 H), 7.61 (dd, J = 8.0 Hz, 1 H), 3.07 (d, J = 8.0 Hz, 1 H), 6.81 (s, 1 H), 3.13 (s, 3 H) 3.14 (br d, J = 16.0 Hz, 1 H), 3.07 (br d, J = 16.0 Hz, 1 H).
13C NMR (100 MHz, DMSO-d 6): δ = 174.9, 142.9, 133.2, 131.9, 127.1, 117.3, 114.8, 111.5, 72.1, 26.6, 26.2.
HRMS: m/z calcd for C11H9BrN2O [M + 2 H]+: 282.0004; found: 281.9950.
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2,2′-(2-Oxoindoline-3,3-diyl)diacetonitrile (4a)[17a]; Typical Procedure
To a stirred mixture of isatin (1a; 0.2 g, 1.36 mmol) in H2O (10 mL) were added ethyl cyanoacetate (2a; 0.290 mL, 2.72 mmol) and DABCO (152 mg, 1.36 mmol), and the reaction mixture was allowed to stir vigorously at 80 °C for 12 h. After TLC had indicated complete consumption of the starting material, the mixture was extracted with EtOAc (3 ×) and the combined organic layers were dried (Na2SO4), and evaporated. The solid was then purified by silica gel column chromatography using EtOAc/hexane (3:7) as an eluent to afford the desired product 4a as a white solid; yield: 186 mg (65%); mp 208–210 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.96 (s, 1 H), 7.52 (d, J = 7.53 Hz, 1 H), 7.33 (td, J = 7.78, 1.25 Hz, 1 H), 7.10 (td, J = 7.53, 0.75 Hz, 1 H), 6.97 (d, J = 7.78 Hz, 1 H), 3.25 (br d, J = 16 Hz, 2 H), 3.11 (br d, J = 18 Hz, 2 H).
13C NMR (100 MHz, DMSO-d 6): δ = 176.0, 142.0, 129.8, 127.9, 123.9, 122.3, 116.5, 110.2, 46.3, 23.5.
HRMS: m/z calcd for C12H9N3O [M + H]+: 212.0824; found: 212.0823.
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2,2′-(5-Chloro-2-oxoindoline-3,3-diyl)diacetonitrile (4b)
White solid; yield: 168 mg (62%); mp 190–192 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 11.45 (s, 1 H), 7.51 (d, J = 8.0 Hz, 1 H), 7.42 (d, J = 8.0 Hz, 1 H), 7.15 (t, J = 7.82 Hz, 1 H), 3.20 (d, J = 16 Hz, 2 H), 3.15 (d, J = 16 Hz, 2 H).
13C NMR (100 MHz, DMSO-d 6): δ =176.5, 140.2, 130.4, 130.2, 124.2, 123.1, 116.9, 114.9, 47.6, 23.9.
HRMS: m/z calcd for C12H8ClN3O [M + H]+: 246.0434; found: 246.0433.
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2,2′-(5-Bromo-2-oxoindoline-3,3-diyl)diacetonitrile (4c)
White solid; yield: 172 mg (67%); mp 180–182 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 11.13 (s, 1 H), 7.78 (d, J = 1.96 Hz, 1 H), 7.53 (dd, J = 8.31, 1.96 Hz, 1 H), 7.14 (d, J = 8.31 Hz, 1 H), 3.31 (d, J = 16.87 Hz, 2 H), 3.15 (br d, J = 16.0 Hz, 2 H).
13C NMR (100 MHz, DMSO-d 6): δ = 176.1, 141.9, 133.1, 130.7, 127.5, 116.9, 114.4, 112.7, 47.2, 23.8.
HRMS: m/z calcd for C12H8BrN3O [M + 2 H]+: 291.0007; found: 290.9932.
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2,2′-(5-Methyl-2-oxoindoline-3,3-diyl)diacetonitrile (4d)
White solid; yield: 145 mg (52%); mp 166–168 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.87 (s, 1 H), 7.35 (s, 1 H), 7.15 (d, J = 7.58 Hz, 1 H), 6.86 (d, J = 7.82 Hz, 1 H), 3.23 (d, J = 16.87 Hz, 2 H), 3.09 (d, J = 16.1 Hz, 2 H), 2.31 (s, 3 H).
13C NMR (100 MHz, DMSO-d 6): δ = 176.5, 140.0, 131.7, 130.6, 128.4, 124.9, 117.1, 110.4, 46.9, 24.1, 21.2.
HRMS: m/z calcd for C13H11N3O [M + H]+: 226.0980; found: 226.0978.
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2,2′-(5-Methoxy-2-oxoindoline-3,3-diyl)diacetonitrile (4e)
White solid; yield: 190 mg (70%); mp 190–192 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.79 (s, 1 H), 7.22 (s, 1 H), 6.86–6.93 (m, 2 H), 3.75 (s, 3 H), 3.75 (s, 3 H), 3.25 (d, J = 16 Hz, 2 H), 3.09 (d, J = 16.63 Hz, 2 H).
13C NMR (100 MHz, DMSO-d 6): δ = 176.3, 155.7, 135.5, 129.6, 117.0, 114.7, 111.6, 111.1, 55.9, 47.3, 24.0.
HRMS: m/z calcd for C13H11N3O2 [M + H]+: 242.0930; found: 242.0928.
#
2,2′-(7-Chloro-2-oxoindoline-3,3-diyl)diacetonitrile (4f)
White solid; yield: 147 mg (54%); mp 162–164 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 11.12 (s, 1 H), 7.66 (d, J = 2.20 Hz, 1 H), 7.41 (dd, J = 8.31, 2.20 Hz, 1 H), 7.41 (dd, J = 8.31, 2.20 Hz, 1 H), 6.99 (d, J = 8.56 Hz, 1 H), 3.31 (br d, J = 16.0 Hz, 2 H), 3.15 (br d, J = 16.0 Hz, 2 H).
13C NMR (100 MHz, DMSO-d 6): δ = 176.2, 141.5, 130.3, 130.3, 126.8, 124.8, 116.9, 112.2, 47.2, 23.8.
HRMS: m/z calcd for C12H8ClN3O [M + H]+: 246.0434; found: 246.0437.
#
2,2′-(7-Bromo-2-oxoindoline-3,3-diyl)diacetonitrile(4g)
Colorless solid; yield: 129 mg (50%); mp 181–183 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.87 (s, 1 H), 7.35 (s, 1 H), 7.15 (d, J = 7.58 Hz, 1 H), 6.86 (d, J = 7.82 Hz, 1 H), 3.23 (d, J = 16.87 Hz, 2 H), 3.09 (d, J = 16.1 Hz, 2 H).
13C NMR (100 MHz, DMSO-d 6): δ = 176.4, 142.0, 133.3, 130.1, 124.5, 123.6, 116.9, 102.9, 47.8, 24.0.
HRMS: m/z calcd for C12H8BrN3O [M + H]+: 289.9929; found: 289.9926.
#
2,2′-(7-Fluoro-2-oxoindoline-3,3-diyl)diacetonitrile (4h)
White solid; yield: 158 mg (57%); mp 189–191 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 11.52 (br s, 1 H), 7.39 (d, J = 7.53 Hz, 1 H), 7.28 (br t, J = 9.54 Hz, 1 H), 7.14 (td, J = 7.78, 5.02 Hz, 1 H), 3.28 (d, J = 16 Hz, 2 H), 3.12 (d, J = 16 Hz, 2 H).
13C NMR (100 MHz, DMSO-d 6): δ = 175.8, 147.6, 145.2, 130.8, 129.0, 123.4, 120.1, 117.1, 116.9, 116.4, 46.8, 23.5.
HRMS: m/z calcd for C12H8FN3O [M + H]+: 230.0730; found: 230.0717.
#
2,2′-(5-Chloro-1-methyl-2-oxoindoline-3,3-diyl)diacetonitrile (4i)
White solid; yield: 165 mg (62%); mp 189–191 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 7.70–7.73 (m, 1 H), 7.53 (dd, J = 8.56, 2.20 Hz, 1 H), 7.20–7.25 (m, 1 H), 3.22 (s, 3 H), 3.20 (d, J = 16 Hz, 2 H), 3.13 (d, J = 16 Hz, 2 H).
13C NMR (100 MHz, DMSO-d 6): δ = 174.4, 142.9, 130.3, 129.5, 127.5, 124.5, 116.8, 111.3, 46.7, 27.0, 23.8.
HRMS: m/z calcd for C13H10ClN3O [M + H]+: 260.0591; found: 260.0589.
#
Ethyl 2-(5-Bromo-3-hydroxy-2-oxoindolin-3-yl)acetate (6c)
To a stirred mixture of 5-bromoisatin (1c; 200 mg, 0.892 mmol) in H2O (10 mL) were added diethyl malonate (2b; 0.136 mL, 0.892 mmol) and DABCO (100 mg, 0.0891 mmol) and the reaction mixture was allowed to stir vigorously at 80 °C for 24 h. After TLC had indicated complete consumption of starting material, the mixture was extracted with EtOAc (3 ×), and the combined organic layers were dried (Na2SO4) and evaporated. The solid was then purified by silica gel column chromatography using EtOAc/hexane (3:7) as an eluent to afford the desired product 6c; yellow solid; yield: 167 mg (60%); mp 185–187 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.42 (br s, 1 H), 7.46–7.59 (m, 1 H), 7.38 (br d, J = 8.31 Hz, 1 H), 6.75 (br d, J = 8.07 Hz, 1 H), 6.26 (s, 1 H), 3.87–3.84 (m, 2 H), 3.09 (br d, J = 15.65 Hz, 1 H), 2.90 (br d, J =16 Hz, 1 H), 0.97 (br t, J = 7.09 Hz, 3 H).
13C NMR (100 MHz, DMSO-d 6): δ = 177.9, 169.0, 142.4, 133.8, 132.3, 127.8, 113.4, 111.9, 73.2, 60.3, 41.8, 14.1.
HRMS: m/z calcd for C12H12BrNO4 [M + H]+: 314.0028; found: 313.9939.
#
#
Acknowledgment
We are thankful to Dr. S. J. S. Flora, Director, NIPER, Raebareli for his support and encouragement in carrying out this research work. C. R. is thankful to the Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India for providing a fellowship. The authors are thankful to Central Instrumentation Facility (CIF), NIPER, Raebareli, and CSIR-CDRI, Lucknow for providing spectral data.
NIPER-R/Communication/083.
Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0040-1707816.
- Supporting Information
-
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- 1c Simon M.-O, Li C.-J. Chem. Soc. Rev. 2012; 41: 1415
- 2a Clark JH, Tavener SJ. Org. Process Res. Dev. 2007; 11: 149
- 2b Sheldon RA. Green Chem. 2005; 7: 267
- 3a Ni J, Sohma Y, Kanai M. Chem. Commun. 2017; 53: 3311
- 3b Kitanosono T, Kobayashi S. Chem. Asian J. 2015; 10: 133
- 3c Kitanosono T, Sakai M, Ueno M, Kobayashi S. Org. Biomol. Chem. 2012; 10: 7134
- 3d Ueno M, Kitanosono T, Sakai M, Kobayashi S. Org. Biomol. Chem. 2011; 9: 3619
- 4a Krapcho AP, Ciganek E. Org. React. 2013; 81: 1
- 4b Poon PS, Banerjee AK, Laya MS. J. Chem. Res. 2011; 35: 67
- 5 Babu PK, Bodireddy MR, Puttaraju RC, Vagae D, Nimmakayala R, Surineni N, Gajula MR, Kumar P. Org. Process Res. Dev. 2018; 22: 773
- 6a Grabowaski K, Baringhaus K.-H, Schneider G. Nat. Prod. Rep. 2008; 25: 892
- 6b Newman DJ, Cragg GM. J. Nat. Prod. Rep. 2016; 79: 629
- 7 Wendeborn S, de Mesmaeker A, Brill WK.-D, Berteina S. Acc. Chem. Res. 2000; 33: 215
- 8a Allred TK, Manoni F, Harran PG. Chem. Rev. 2017; 117: 11994
- 8b DeCorte BL. J. Med. Chem. 2016; 59: 9295
- 8c Butler MS. J. Nat. Prod. 2004; 67: 2141
- 8d Kingston DG. I. J. Nat. Prod. 2011; 74: 496
- 9a Yu B, Xing H, Yu D.-Q, Liu H.-M. Beilstein J. Org. Chem. 2016; 12: 1000
- 9b MacDonald JP, Badillo JJ, Arevalo GE, Silva-Garcia A, Franz AK. ACS Comb. Sci. 2012; 14: 285
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- 18e Tiwari KN, Thakar SR, Kumar V, Prabhakaran SM. Synth. Commun. 2018; 48: 2965
- 19a Romney DK, Arnold FH, Lipshutz BH, Li C.-J. J. Org. Chem. 2018; 83: 7319
- 19b Sela T, Vigalok A. Org. Lett. 2014; 16: 1964
- 19c Manna A, Kumar A. J. Phys. Chem. A. 2013; 117: 2446
- 19d Jung Y, Marcus RA. J. Am. Chem. Soc. 2007; 129: 5492
- 20 Deng T, Wang H, Cai C. Eur. J. Org. Chem. 2014; 32: 7259
- 21 Gajulapalli VP. R, Vinyagam P, Kesavan V. Org. Biomol. Chem. 2014; 12: 4186
- 22 Sharma P, Senwar KR, Jeengar MK, Reddy TS, Naidu VG. M, Kamal A, Shankaraiah N. Eur. J. Med. Chem. 2015; 104: 11
