Direct alkenylation of indolin-2-ones by 6-aryl-4-methylthio-2H-pyran-2-one-3-carbonitriles: a novel approach

A direct one-pot base-induced alkenylation of indolin-2-ones has been developed by using 6-aryl-4-methylthio-2H-pyran-2-one-3-carbonitriles. Different bases such as MeONa, NaH and t-BuONa have been used to optimize the reaction conditions to obtain the desired product. NaH in THF was found to be the most suitable for the alkenylation of indolin-2-ones. Reaction in the presence of other bases led to the formation of 1-aryl-3-methoxy/methylthio-5H-dibenzo[d,f][1,3]diazepin-6(7H)-ones. Quantum chemical calculations have been performed to explain the nature of the weak noncovalent interactions operating in the supramolecular architectures of alkenylated indoline-2-ones and to explain the relative stability of one of the tautomers with respect to the others.

Further, reactions of 3 and 4 in the presence of NaH as a base in THF under reflux gave a product entirely different from 5, 6 and 7. The isolated product was finally characterized by singlecrystal X-ray diffraction as (2Z,5E)-5-aryl-3-methylthio-5-(2oxoindolin-3-ylidene)pent-2-enenitrile 8. The reaction is initiated with Michael addition at C6 followed by ring opening with elimination of carbon dioxide to deliver product 8 without undergoing further cyclization to yield either 6 or 7, possibly due to the lower dielectric constant of THF (7.42) compared to methanol (32.7) (Scheme 3). As is evident from Scheme 3, there are three possible tautomeric forms for 8, viz. 8x, 8y, 8z for the isolated compound. Single-crystal X-ray studies revealed that out of the three tautomeric forms, the 8y is the most suitable structure based on the bond lengths. Quantum chemical calculations have been performed in order to gain information regarding the relative energy difference, which in turn reflects the relative stability between the tautomeric forms 8x, 8y and 8z. The energy calculations at the DFT level of theory for all of the three tautomers indicate that 8y is 17.07 kJ·mol −1 more stable than 8x, and it is more stable than 8z by 14.84 kJ·mol −1 . A deep structural study of 8y indicates the formation of intramolecular C-H … O interaction which may be responsible for its extra stability compared to 8x and 8z. However, for 8z the formation of intramolecular C-H … O interactions is also possible, but the existence of the relatively more stable trans-8z nullifies the likelihood of this type of interaction. Hence, density functional theory (DFT) calculations also indicate that the tautomer 8y is relatively more stable than 8x and 8z ( Figure 2).
Further, in order to generalize the reaction, attempts were made for the alkenylation of indolin-2-one with 6-aryl-4-sec-amino-2H-pyran-2-one-3-carbonitriles 9 [41,42], obtained by the amination of 3 with sec-amine in boiling ethanol to yield a secamino substituted alkenylated chain on position 3 of the indolin-2-one (4). But to our utmost surprise the expected alkenylated product 11 could not be isolated. However, in lieu of this, the product isolated was characterized as 1-aryl-3-secamino-5H-dibenzo[d,f][1,3]diazepin-6(7H)-one 10. The formation of 10 is possible only if the reaction is initiated with Michael addition of indolin-2-one at C6 not at C4, due to the presence of the secondary amino group, which reduces its electrophilicity. Thus, preferential attack by carbanion generated from 4 at C6 was inevitable for the formation of 10 (Scheme 4).

X-ray crystallography
The molecular view (ORTEP) for the compounds 8yc with its atom numbering scheme is presented in Figure 2. The compound 8yc crystallizes in a monoclinic crystal system having P2 1 /c space group with four molecules in the unit cell. The rings A and B are coplanar with respect to each other. However, the dihedral angle between the rings A and C is 73.52°. The bond lengths C2-C9, C9-C10, C9-C15, C10-C11 and C11-C12 have dimensions 1.348(5), 1.513(5), 1.501 (7) In order to analyze the various interactions that lead to the crystal structure, interaction energies and electrostatic potentials were calculated for dimer fragments ( Figure 5). The analysis of the interaction energy in the crystal structures of 8yc by means of the dimer unit bound by C-H … π, C-H … O and Ar-H … π interactions at the DFT level of theory yields interaction energies of 22.33, 14.92 and 15.45 kJ·mol −1 , respectively. To confirm further the presence of these weak interactions, bond critical points (bcp) were calculated for the different dimers by using the atoms in molecules theory [43]. The bond critical points observed between the interacting atoms confirm the presence of weak noncovalent interactions between the two molecules of 8yc. The value of electron density (ρ), Laplacian of the electron density ( ρ bcp ), bond ellipticity (ε), electron density (ρ), and total energy density (H) at the bond critical point for all the three interactions are presented in Table 1. As indicated in Table 1, the electron densities for all the three types of interactions at the bond critical point (ρ bcp ) are less than +0.10 au, which indicates closed-shell hydrogen bonding interactions. Additionally, the Laplacians of the electron density ρ bcp in all the three cases are greater than zero, which indicates the depletion of electron density in the region of contact between the H … O and H … C atoms. The bond ellipticity (ε) measures the extent to which the density is preferentially accumulated in a given plane containing the bond path. The ε values for all the three interactions indicate that these are not cylindrically symmetrical in nature.

Conclusion
Owing to the numerous procedures known for the synthesis of 3-alkenyl-2-oxindoles being based on expensive catalysts, noncommercially available precursors, and multistep timeconsuming synthetic protocols, the development of an efficient, economical and short synthesis was inevitable and desirable. In this regard, we have now developed an efficient new protocol for the direct alkenylation of 2-oxindole by 6-aryl-4-methylthio-2H-pyran-2-one-3-carbonitriles 3 to deliver 3-alkenyl-2-oxindoles 8 in moderate yield. This procedure is quite efficient, noncatalytic, economical and easy in workup. Moreover, it opens a new avenue for the synthesis of 3-alkenyl-2-oxindoles. Furthermore, the synthesis of 8y and its relative stability with respect to the other tautomers has been confirmed by singlecrystal X-ray analysis and quantum chemical calculations. X-ray diffraction displayed various C−H … π, C−H … O and Ar-H … π intermolecular interactions. These interactions have been evaluated by quantum chemical calculations.

Experimental General
The reagents and the solvents used in this study were of analytical grade and used without further purification. The melting points were determined on an electrically heated Townson Mercer melting point apparatus and are uncorrected. Commercial reagents were used without purification. 1

Synthesis of 1-phenyl-3-(methylthio)-5Hdibenzo[d,f][1,3]diazepin-6(7H)-one (5)
A mixture of indoline-2-one (4, 1.1 mmol) and 2-pyranone (3, 1.0 mmol) and t-BuOK (2.1 mmol) in methanol/t-BuOH (10 mL) was heated under reflux for 6 h and was monitored by TLC. After completion of the reaction, the excess of solvent was removed under reduced pressure and the reaction mixture was poured onto crushed ice with vigorous stirring. The aqueous reaction mixture was neutralized with dilute HCl and the resulting precipitate was filtered, washed with water and dried. The crude product was purified by silica gel column chromatography using chloroform/hexane as eluent to afford product 5 (analytical data and spectra are given in Supporting Information File 1 and Supporting Information File 2).
General procedure for the synthesis of alkenylindoline-2-ones 8y A mixture of sodium hydride (2.1 mmol), indolin-2-one (4, 1.1 mmol) and lactone 3 (1.0 mmol) in dry THF (10 mL) was heated under reflux for 4-5 h. The excess of THF was removed under reduced pressure, and the reaction mixture was poured onto crushed ice with vigorous stirring. The aqueous reaction mixture was neutralized with dilute HCl. The precipitate obtained was filtered, washed with water, and dried. The isolated crude product 8y was purified by silica gel column chromatography using hexane/chloroform as eluent to afford products 8ya-8yj (the analytical data and spectra are given in Supporting Information File 1 and Supporting Information File 2).
General procedure for the synthesis of 1-aryl-3-(sec-amino)-5H-dibenzo[d,f] [1,3]diazepin-6(7H)-one (10) A mixture of lactone (9, 1.0 mmol) sodium hydride (2.1 mmol), and indolin-2-one (4, 1.1 mmol) in dry THF (10 mL) was heated under reflux for 4-5 h. The excess of solvent was removed under reduced pressure, and the reaction mixture was poured into ice-cold water under vigorous stirring. The aqueous mixture was neutralized with dilute HCl, and the precipitate obtained was filtered, washed with water, and dried. The isolated product was purified by silica gel column chromatography using hexane/chloroform as eluent to afford products 10a and 10b (the analytical data and spectra are given in Supporting Information File 1 and Supporting Information File 2).

Structure determination
Intensity data for the yellow colored crystals of 8y and 5 were collected at 298(2) K on an OXFORD CrysAlis diffractometer system equipped with a graphite-monochromated Mo Kα radiation source, λ = 0.71073 Å. The final unit cell determination, scaling of the data, and corrections for Lorentz and polarization effects were performed with CrysAlis RED [44]. The structures were solved by direct methods (SHELXS-97) [45] and refined by a full-matrix least-squares procedure based on F 2 [46]. All the calculations were carried out using WinGX system Ver-1.64 [47]. All nonhydrogen atoms were refined anisotropically; hydrogen atoms were located at calculated positions and refined using a riding model with isotropic thermal parameters fixed at 1.2 times the U eq value of the appropriate carrier atom.
Crystal data for compound 5

Computational details
Geometric characterization of all of the three tautomers of 8yc was performed at the level of density functional theory (DFT) using the B3LYP functional [48,49]. For all the atoms 6-31G** basis sets were used. All calculations were performed using the Gaussian 03 program [50]. The intermolecular interaction energies were estimated at the MP2 level of theory. For the inter-action energy calculations, the C-H … π, Ar-H … π and Ar-H … O distances were fixed for the dimer while all other degrees of freedom were relaxed in the geometry optimization. The magnitude of the energy corresponding to this dimer was subtracted from twice the energy of the monomer. The intermolecular interaction strengths are significantly weaker than either ionic or covalent bonding, therefore it was essential to perform basis set superposition error (BSSE) corrections. The BSSE corrections in the interaction energies were carried out using Boys-Bernardi scheme [51]. In this paper all interaction energies are reported after BSSE correction.

Supporting Information
The Supporting Information features the analytical data and copies of 13