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One-Pot Synthesis of (E)-2-(3-Oxoindolin-2-ylidene)-2-arylacetonitriles

A highly efficient and expeditious one-pot approach towards 2-(3-oxoindolin-2-yl)acetonitriles was designed, which involves a base-assisted aldol reaction of ortho-nitroacetophenones, followed by hydrocyanation, triggering an unusual reductive cyclization reaction.


Introduction
The derivatives of 2-Alkylideneindolin-3-one play important role in modern medicinal chemistry. The bis-indole indirubin known as "Tyrian purple" dye has been used for many years as an active component of a traditional Chinese herbal medicine [1][2][3]. Lately, numerous synthetic analogs of this compound were reported to show potent and highly selective pharmacological inhibition of glycogen synthase kinases and cycline-dependent kinases [4][5][6]. Related compounds possessing a single 3-oxoindoline subunit (or two remotely positioned subunits) also were isolated from natural sources and are also known to exhibit a wide spectrum of important biological properties [7][8][9][10][11][12][13]. Normally, the preparation of these structures relies heavily on the chemistry of isatins, which greatly limits the diversity of accessible substitution patterns. Alternative methods have also been developed based on the aldol condensation of 3H-indol-3-ones with carbonyl compounds [14][15][16][17], the transition metal-catalyzed carbonylative cross-coupling of ortho-iodoanilines to alkynes [18][19][20][21], or the cascade cyclizations of anilines with α-ketoesters [7,22]. We recently reported an original, facile, and highly efficient method for the preparation of 2-(3-oxoindolin-2-ylidene) acetonitriles 2 from ortho-nitrochalcones 1, operating as a triggered Michael addition of the cyanide anion to the chalcone followed by a cascade cyclization mechanistically related to the Baeyer-Drewson reaction (Scheme 1) [23].

Introduction
The derivatives of 2-Alkylideneindolin-3-one play important role in modern medicinal chemistry. The bis-indole indirubin known as "Tyrian purple" dye has been used for many years as an active component of a traditional Chinese herbal medicine [1][2][3]. Lately, numerous synthetic analogs of this compound were reported to show potent and highly selective pharmacological inhibition of glycogen synthase kinases and cycline-dependent kinases [4][5][6]. Related compounds possessing a single 3-oxoindoline subunit (or two remotely positioned subunits) also were isolated from natural sources and are also known to exhibit a wide spectrum of important biological properties [7][8][9][10][11][12][13]. Normally, the preparation of these structures relies heavily on the chemistry of isatins, which greatly limits the diversity of accessible substitution patterns. Alternative methods have also been developed based on the aldol condensation of 3H-indol-3-ones with carbonyl compounds [14][15][16][17], the transition metal-catalyzed carbonylative cross-coupling of ortho-iodoanilines to alkynes [18][19][20][21], or the cascade cyclizations of anilines with -ketoesters [7,22]. We recently reported an original, facile, and highly efficient method for the preparation of 2-(3oxoindolin-2-ylidene) acetonitriles 2 from ortho-nitrochalcones 1, operating as a triggered Michael addition of the cyanide anion to the chalcone followed by a cascade cyclization mechanistically related to the Baeyer-Drewson reaction (Scheme 1) [23].
Herein, we report on the development of a more streamlined synthetic approach which allows for the combining of this transformation with the preparation of the chalcone precursor 1 from aldehydes 4 and ortho-nitroacetophenones 3 in a single one-pot operation.

Results and Discussion
Since our newly developed method for preparation of 2-(3-oxoindolin-2-ylidene) acetonitriles 2 relies heavily on the availability of the corresponding chalchone precursors 1, we wondered about possibility of generating them in situ via an aldol condensation reaction. It was initially planned that this step could be carried out in the presence of catalytic amounts of alkali, which later would be neutralized with acetic acid to trigger the hydrocyanation step. However, much more attractive was the idea of employing potassium cyanide as a base to catalyze the aldol condensation step. This unusual approach to the aldol reaction was precedented in a single report by Migita et al. [24]. To test this idea, we subjected 2-nitroacetophenone (2a) to the reaction with p-anisaldehyde (4a) in the presence of KCN in methanol (2 mL). Water additive (130 µL) was used, as it was previously demonstrated it is crucial for successful cyclization [23]. The reaction mixture was refluxed for 1 h, then treated with acetic acid (150 µL) and refluxed for an additional 30 min to afford 3-oxoindoline 2aa in 64% yield ( Table 1, entry 1). This reaction was accompanied by the formation of a large number of unidentified side products, as evidenced by TLC analysis. In attempt to improve this situation, we decided to carry out the reaction under conditions ensuring a faster kinetic rate of the desired transformation. First, cyanide loading was increased (with a proportional increase of water and acetic acid concentrations). The reaction proceeded faster, but the yield of the target product was not improved under these conditions (entry 2). Then, the concentration effect was evaluated, with the knowledge that this effect should be favorable for bimolecular reactions. Indeed, when the concentration of starting materials was increased twice, 2aa was formed cleanly in 95% yield (entry 3). Finally, it was found that decreasing the temperature had a detrimental effect on the reaction performance. The reaction proceeded very sluggishly, affording 2aa in 58% yield along with several unidentified side products (entry 4). Without water additive, this reaction affords lower yields (entry 5), and this is also the case when other acids are employed instead of acetic (entries 6, 7). Herein, we report on the development of a more streamlined synthetic approach which allows for the combining of this transformation with the preparation of the chalcone precursor 1 from aldehydes 4 and ortho-nitroacetophenones 3 in a single one-pot operation.

Results and Discussion
Since our newly developed method for preparation of 2-(3-oxoindolin-2-ylidene) acetonitriles 2 relies heavily on the availability of the corresponding chalchone precursors 1, we wondered about possibility of generating them in situ via an aldol condensation reaction. It was initially planned that this step could be carried out in the presence of catalytic amounts of alkali, which later would be neutralized with acetic acid to trigger the hydrocyanation step. However, much more attractive was the idea of employing potassium cyanide as a base to catalyze the aldol condensation step. This unusual approach to the aldol reaction was precedented in a single report by Migita et al. [24]. To test this idea, we subjected 2-nitroacetophenone (2a) to the reaction with p-anisaldehyde (4a) in the presence of KCN in methanol (2 mL). Water additive (130 μL) was used, as it was previously demonstrated it is crucial for successful cyclization [23]. The reaction mixture was refluxed for 1 h, then treated with acetic acid (150 μL) and refluxed for an additional 30 min to afford 3-oxoindoline 2aa in 64% yield ( Table 1, entry 1). This reaction was accompanied by the formation of a large number of unidentified side products, as evidenced by TLC analysis. In attempt to improve this situation, we decided to carry out the reaction under conditions ensuring a faster kinetic rate of the desired transformation. First, cyanide loading was increased (with a proportional increase of water and acetic acid concentrations). The reaction proceeded faster, but the yield of the target product was not improved under these conditions (entry 2). Then, the concentration effect was evaluated, with the knowledge that this effect should be favorable for bimolecular reactions. Indeed, when the concentration of starting materials was increased twice, 2aa was formed cleanly in 95% yield (entry 3). Finally, it was found that decreasing the temperature had a detrimental effect on the reaction performance. The reaction proceeded very sluggishly, affording 2aa in 58% yield along with several unidentified side products (entry 4). Without water additive, this reaction affords lower yields (entry 5), and this is also the case when other acids are employed instead of acetic (entries 6, 7). Table 1. Optimization of the reaction conditions for one-pot conversion of 2-nitroacetophenone (3a) and p-anisaldehyde (4a) into (E)-2-(3-oxoindolin-2-ylidene)-2-arylacetonitriles (2aa). With the optimized conditions in hand, we performed these transformations in a preparative scale (up to 2.00 mmol) and managed to obtain comparably high isolated yields of 2aa (85%) ( Table 1, entry 3, Scheme 2). The reaction demonstrated good tolerance and compatibility with a variety of substituents, including alkoxyarenes, halogenated arenes, and cyclic acetals (Scheme 2). The formation of (E)-2-(3-oxoindolin-2-ylidene)acetonitrile moiety in this reaction was unambiguously confirmed by single crystal X-ray diffraction of compound 2al (CCDC #2157035, Figure 1).

KCN a Temperature (°C)/Time (h) Methanol/Water/AcOH
With the optimized conditions in hand, we performed these transformations in a preparative scale (up to 2.00 mmol) and managed to obtain comparably high isolated yields of 2aa (85%) ( Table 1, entry 3, Scheme 2). The reaction demonstrated good tolerance and compatibility with a variety of substituents, including alkoxyarenes, halogenated arenes, and cyclic acetals (Scheme 2). The formation of (E)-2-(3-oxoindolin-2-ylidene)acetonitrile moiety in this reaction was unambiguously confirmed by single crystal X-ray diffraction of compound 2al (CCDC #2157035, Figure 1).

Scheme 2. Preparation of 2-(3-oxoindolin-2-yl)acetonitriles 2. Scheme 2. Preparation of 2-(3-oxoindolin-2-yl)acetonitriles 2.
It was possible to engage heterocyclic aldehydes into the featured transformation. Thus, the reaction of ortho-nitroacetophenone (3a) with thiophene-2-carbaldehyde (4o) afforded thienyl-substituted compound 2ao in good yield (Scheme 3). On the other hand, the reaction involving benzo[b]thiophene-3-carbaldehyde (4p) led to the formation of rearranged polycyclic product 2ap (Scheme 3). Further investigation of this unusual transformation is currently under way in our laboratories. It was possible to engage heterocyclic aldehydes into the featured transformation. Thus, the reaction of ortho-nitroacetophenone (3a) with thiophene-2-carbaldehyde (4o) afforded thienyl-substituted compound 2ao in good yield (Scheme 3). On the other hand, the reaction involving benzo[b]thiophene-3-carbaldehyde (4p) led to the formation of rearranged polycyclic product 2ap (Scheme 3). Further investigation of this unusual transformation is currently under way in our laboratories. The mechanistic rationale for the featured transformation is shown in Scheme 4. It is believed that potassium cyanide can serve as a base to induce the enolization of orthonitroacetophenone 3 to provide enolate form 5, which can be engaged into an aldol reaction with aldehyde 4 affording chalchone 1 (Scheme 4). The subsequent conjugate addition of cyanide to chalchone would provide 4-oxo-4-arylbutanenitrile in enolate form 6.
To demonstrate the possibility of carrying out this sequence of reactions, we tested the reactivity between acetophenone (11) and benzaldehyde (4b) in the presence of excess potassium cyanide under typical reaction conditions. Expectedly, 4-oxo-4-phenylbutanenitrile 12 was formed smoothly, albeit in marginal yield (Scheme 5). Once formed, enolate species 6 would experience intramolecular nucleophilic attack involving the ortho-nitro group to afford cyclic keto-azinate 7, which should exist in tautomeric equilibrium with azinic acid-enolate   The mechanistic rationale for the featured transformation is shown in Scheme 4. It is believed that potassium cyanide can serve as a base to induce the enolization of orthonitroacetophenone 3 to provide enolate form 5, which can be engaged into an aldol reaction with aldehyde 4 affording chalchone 1 (Scheme 4). The subsequent conjugate addition of cyanide to chalchone would provide 4-oxo-4-arylbutanenitrile in enolate form 6.
To demonstrate the possibility of carrying out this sequence of reactions, we tested the reactivity between acetophenone (11) and benzaldehyde (4b) in the presence of excess potassium cyanide under typical reaction conditions. Expectedly, 4-oxo-4-phenylbutanenitrile 12 was formed smoothly, albeit in marginal yield (Scheme 5). Once formed, enolate species 6 would experience intramolecular nucleophilic attack involving the ortho-nitro group to afford cyclic keto-azinate 7, which should exist in tautomeric equilibrium with azinic acid-enolate form 8 (Scheme 4). The elimination of the hydroxyl group from this species would lead to the formation of imine N-oxide intermediate 9, which should tautomerize into cyclic hydroxylamine 10. Subsequent reduction (most likely involving methanol as a reducing agent) [25]  The mechanistic rationale for the featured transformation is shown in Scheme 4. It is believed that potassium cyanide can serve as a base to induce the enolization of orthonitroacetophenone 3 to provide enolate form 5, which can be engaged into an aldol reaction with aldehyde 4 affording chalchone 1 (Scheme 4). The subsequent conjugate addition of cyanide to chalchone would provide 4-oxo-4-arylbutanenitrile in enolate form 6. To demonstrate the possibility of carrying out this sequence of reactions, we tested the reactivity between acetophenone (11) and benzaldehyde (4b) in the presence of excess potassium cyanide under typical reaction conditions. Expectedly, 4-oxo-4-phenylbutanenitrile 12 was formed smoothly, albeit in marginal yield (Scheme 5). Once formed, enolate species 6 would experience intramolecular nucleophilic attack involving the ortho-nitro group to afford cyclic keto-azinate 7, which should exist in tautomeric equilibrium with azinic acid-enolate form 8 (Scheme 4). The elimination of the hydroxyl group from this species would lead to the formation of imine N-oxide intermediate 9, which should tautomerize into cyclic hydroxylamine 10. Subsequent reduction (most likely involving methanol as a reducing agent) [25] would afford final 2-(3-oxoindolin-2-yl)acetonitriles 2 (Scheme 4) [23]. It should be pointed out that carrying out a reaction between ortho-nitroacetophenone 3a and benzaldehyde 4b followed by quenching with phenacyl bromide (serving as a precursor of HBr, slowly released over an extended period) allowed for the isolation of compound 10ab in moderate yield (Scheme 6). The same compound was detected by mass spectroscopy in the reaction mixture carried out under standard conditions. It proved to be stable upon heating in DMSO at 100 • C for 2 hr. However, treatment of this sample with water or formic acid caused the slow consumption of 10ab (mass 285 [M + Na]) and accumulation of product 2ab (mass 269 [M + Na]). In the presence of methanol and acetic acid, this process proceeded notably faster. In preparative scale, this reaction afforded a nearly quantitative conversion into 2ab, identical to the sample obtained in one-pot fashion (Scheme 6).
(Scheme 4) [23]. It should be pointed out that carrying out a reaction between ortho-nitroacetophenone 3a and benzaldehyde 4b followed by quenching with phenacyl bromide (serving as a precursor of HBr, slowly released over an extended period) allowed for the isolation of compound 10ab in moderate yield (Scheme 6). The same compound was detected by mass spectroscopy in the reaction mixture carried out under standard conditions. It proved to be stable upon heating in DMSO at 100 °C for 2 hr. However, treatment of this sample with water or formic acid caused the slow consumption of 10ab (mass 285 [M + Na]) and accumulation of product 2ab (mass 269 [M + Na]). In the presence of methanol and acetic acid, this process proceeded notably faster. In preparative scale, this reaction afforded a nearly quantitative conversion into 2ab, identical to the sample obtained in one-pot fashion (Scheme 6).

Conclusions
An improved protocol for the preparation of 2-(3-oxoindolin-2-yl)acetonitriles 2 via a cyanide-mediated cascade reaction of ortho-nitroacetophenones (3) with aromatic aldehydes (4) was developed. This transformation involves an initial aldol condensation followed by a Michael-type conjugated addition of cyanide anion to the intermediate chalcone, which triggers an unusual cyclization mechanistically related to the Baeyer-Drewson reaction. This methodology was employed to synthesize a small, focused library acetophenone 3a and benzaldehyde 4b followed by quenching with phenacyl bromide (serving as a precursor of HBr, slowly released over an extended period) allowed for the isolation of compound 10ab in moderate yield (Scheme 6). The same compound was detected by mass spectroscopy in the reaction mixture carried out under standard conditions. It proved to be stable upon heating in DMSO at 100 °C for 2 hr. However, treatment of this sample with water or formic acid caused the slow consumption of 10ab (mass 285 [M + Na]) and accumulation of product 2ab (mass 269 [M + Na]). In the presence of methanol and acetic acid, this process proceeded notably faster. In preparative scale, this reaction afforded a nearly quantitative conversion into 2ab, identical to the sample obtained in one-pot fashion (Scheme 6).

Conclusions
An improved protocol for the preparation of 2-(3-oxoindolin-2-yl)acetonitriles 2 via a cyanide-mediated cascade reaction of ortho-nitroacetophenones (3) with aromatic aldehydes (4) was developed. This transformation involves an initial aldol condensation followed by a Michael-type conjugated addition of cyanide anion to the intermediate chalcone, which triggers an unusual cyclization mechanistically related to the Baeyer-Drewson reaction. This methodology was employed to synthesize a small, focused library acetophenone 3a and benzaldehyde 4b followed by quenching with phenacyl bromide (serving as a precursor of HBr, slowly released over an extended period) allowed for the isolation of compound 10ab in moderate yield (Scheme 6). The same compound was detected by mass spectroscopy in the reaction mixture carried out under standard conditions. It proved to be stable upon heating in DMSO at 100 °C for 2 hr. However, treatment of this sample with water or formic acid caused the slow consumption of 10ab (mass 285 [M + Na]) and accumulation of product 2ab (mass 269 [M + Na]). In the presence of methanol and acetic acid, this process proceeded notably faster. In preparative scale, this reaction afforded a nearly quantitative conversion into 2ab, identical to the sample obtained in one-pot fashion (Scheme 6).

Conclusions
An improved protocol for the preparation of 2-(3-oxoindolin-2-yl)acetonitriles 2 via a cyanide-mediated cascade reaction of ortho-nitroacetophenones (3) with aromatic aldehydes (4) was developed. This transformation involves an initial aldol condensation followed by a Michael-type conjugated addition of cyanide anion to the intermediate chalcone, which triggers an unusual cyclization mechanistically related to the Baeyer-Drewson reaction. This methodology was employed to synthesize a small, focused library

Conclusions
An improved protocol for the preparation of 2-(3-oxoindolin-2-yl)acetonitriles 2 via a cyanide-mediated cascade reaction of ortho-nitroacetophenones (3) with aromatic aldehydes (4) was developed. This transformation involves an initial aldol condensation followed by a Michael-type conjugated addition of cyanide anion to the intermediate chalcone, which triggers an unusual cyclization mechanistically related to the Baeyer-Drewson reaction. This methodology was employed to synthesize a small, focused library of target molecules. It should be mentioned that aliphatic aldehydes do not participate in aldol condensation under these reaction conditions and cannot be used as precursors for preparation of alkylsubstituted analogs. An investigation into the biological activity of these new €-2-(3oxoindolin-2-ylidene)-2-arylacetonitriles is currently under way in our laboratories.

Experimental Part General
NMR spectra ( 1 H and 13 C) were measured in solutions of CDCl 3 or DMSO-d 6 on a Bruker AVANCE-III HD instrument (at 400.40 or 100.61 MHz, respectively). HRMS spectra were measured in MeCN solutions on Bruker maXis impact (electrospray ionization, employing HCO 2 Na-HCO 2 H for calibration). See Supplementary Materials for NMR and HRMS spectral charts and X-Ray crystallography data. IR spectra was measured on an FT-IR spectrometer Shimadzu IRAffinity-1S equipped with an ATR sampling module. Reaction progress, purity of isolated compounds, and R f values were assessed by TLC on Silufol UV-254 plates. Column chromatography was performed on silica gel (32-63 µm, 60 Å pore size). Melting points were measured on Stuart SMP30 apparatus. All reagents and solvents were purchased from commercial vendors and used as received. The reactions involving KCN are accompanied by the formation of highly toxic fumes of HCN. A well-ventilated fume hood must be used.