An Efficient Synthesis of a Spirocyclic Oxindole Analogue

An efficient, scaleable synthesis approach towards the spirocyclic oxindole analogue


Results and Discussion
The synthetic plan for the synthesis of the target molecule is outlined in Scheme 1.Our first objective was synthesis of the substituted oxindole 4. Of the reported synthetic routes to oxindoles [7], Lewis acid catalyzed cyclization of α-haloacetanilides [8] was proposed as the most efficient route to synthesize 4, but in practice this method gave a rather low yield (<10%), due to the strongly acidic conditions used in the transformation.Next, the synthesis of the target oxindole via the intermediacy of an azasulfonium salt [9] was investigated for its relatively mild conditions.Ethyl 4-aminobenzoate 2 was sequentially treated with tert-butyl hypochlorite, ethyl(methylthio) acetate and triethylamine, followed by dilute hydrochloric acid, to give substituted 3-methylthiooxindole 3 in 75% yield.Reductive desulfurization of 3 with Raney Ni afforded the target 4 in 85% yield.Now we turned to the key step, the synthesis of the spirocyclic oxoindole 5. Goehring and others [5,10] have reported that treatment of a non substituted oxindole with excess sodium hexamethyldisilazide gave an oxoindole dianion [11], which when alkylated with N-methylbis(2chloroethyl)amine afforded the corresponding spirocyclic oxindole.Unfortunately, in our case these conditions gave rather low yields.We found that the alkylation is difficult with various bases such as sodium hexamethyldisilazide, lithium hexamethyldisilazide, lithium diisopropylamide and potassium tert-butoxide in solvents such as tetrahydrofuran and dimethylformamide [12].The low yields are due to the presence in 4 of the electron-withdrawing carboxylic ester group, which decreases the nucleophilicity of the enolate anion.Eventually we found that treatment of 4 with 4.5 equivalents of sodium hydride and dichloroethylmine hydrochloride in dimethylformamide for 5 hours gave the desired product 5 in 65% yield.With this intermediate in hand, we next embarked on the demethylation of 5 [13].It is worth noting that, in our hands, attempts to alkylate the oxindole dianion with either N-Boc or N-benzyl dichloroethamine (to potentially shorten the synthesis) met with no success.However, treatment of 5 with 2,2,2-trichloroethyl chloroformate (TCE-Cl), followed by zinc reduction and subsequent Boc protection, gave a low yield (31%) of the desired protected amine 6.

Scheme 1
After detailed investigation of the process, we found the following (Scheme 2): a) when 5 was treated with TCE-Cl, the mono-acylated intermediate 7 is first formed quantitatively, but it cannot be completely converted to 9, even when excess TCE-Cl is added.The acid, which was formed in situ during the formation of 7, would most likely result in the competition between the formation of hydrochloric salt 10, which would no longer react with TCE-Cl, and quaternary salt intermediate 8, which will lead to the desired di-acylated intermediate 9; b) when 7 was isolated and treated with TCE-Cl, the reaction is still reversible even under reflux conditions.This strongly indicates that the quaternary salt intermediate 8 undergoes two competitive reactions [13d], namely nucleophilic attack of the chloride ion on the O-alkyl portion, which has no net effect on 7, and nucleophilic attack of the chloride ion on the methyl group, leading to 9; c) eventually we found that upon treatment of 5 with 1-1.5 eq.triethylamine, followed by addition of TCE-Cl, the desired intermediate 9 was formed quantitatively and the reaction was complete in less than 10 minutes.These results suggest that triethylamine not only neutralizes the hydrochloric acid generated during the formation of 7, but also has significant influence on the breakup of quaternary salt 8. Presumably triethylamine is chelated with the chloride ion.The nucleophilic attack of the chelated chloride ion on the O-alkyl portion is then disfavored due to steric hindrance.To test the hypothesis, we investigated the dealkylation of Nethylpiperidine, which was most often reported as the standard substrate for dealkylation [13b].The report yield is less than 10% when TCE-Cl was used.As we expected, when one equivalent of triethylamine hydrochloride was added in the reaction mixture, the dealkylation was finished within 30 minutes with 95% yields.Finally, upon zinc reduction and subsequent Boc protection, the spirocyclic oxindole 6 was obtained in 92% from 5. Saponification of 6 gave 1 in 91% yield.

General
All commercially available chemicals and reagents were used without further purification.The 1 Hand 13 C-NMR spectra were recorded on Bruker DPX-300 spectrometer.Chemical shifts (δ) are reported in ppm and are referenced to the deuterium solvent residual peak (for 1 H-NMR, δ is 7.26 in CDCl 3 and 2.50 in DMSO-d 6 , respectively; for 13 C-NMR, δ is 77.2 in CDCl 3 and 39.5 in DMSO-d 6 , respectively).Mass spectral analyses were performed by the Institute for Biomolecular Design of University of Alberta using an Applied Biosystems Voyager System 6064.TLC analysis was facilitated by the use of the following stains in addition to UV light with fluorescent-indicating plates (silica gel on glass, Silicycle): phosphomolybdic acid, anisaldehyde/EtOH, or KMnO 4 /H 2 O.

Ethyl 3-(methylthio)-2-oxindoline-5-carboxylate (3).
To a solution of ethyl 4-aminobenzoate 2 (30.0 g, 0.182 mol) in dichloromethane (600 mL) at 0 o C was added a solution of tert-butylhypochlorite (19.8 g, 0.182 mol) in dichloromethane (80 mL).The reaction mixture was stirred for 10 minutes and cooled to -65 °C.A solution of ethyl (methylthio) acetate (24.4 g, 0.182 mol) in dichloromethane (80 mL) was added dropwise and the reaction mixture was stirred for 1 hour, then a solution of triethylamine (18.4 g, 0.182 mol) in dichloromethane (80 mL) was added and the reaction mixture was warmed to room temperature.To this mixture was added water (300 mL) and the phases were separated.The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated.The residue was dissolved in ether (600 mL) to which 2N HCl (80 mL) was added and the mixture was stirred for 18 hours.The solid formed was collected by filtration, washed with a small amount of hexane and dried in a vacuum oven to afford 3 (34.3g, 75%) as an off white solid; To a solution of ethyl 3-(methylthio)-2-oxindoline-5-carboxylate 3 (60.0g, 0.239 mol) in absolute ethanol (1200 mL) was added Raney Nickel 2800 (60 g).The reaction mixture was heated to reflux for 4 hours and quickly filtered while it was still hot.The filtrate was concentrated to half its volume and the product was crystallized.The solid was filtered and dried in a vacuum oven to afford 4 (41.6 g, 85 %) as a white solid;

Ethyl 1'-methyl-2-oxospiro[indoline-3,4'-piperidine]-5-carboxylate (5)
To a solution of oxindole 4 (26.7 g, 0.130 mol) in dry dimethylformamide (900 mL) at 0 °C was added sodium hydride (14.1 g, 0.585 mol).The reaction mixture was stirred for 10 minutes.Dichloethylamine hydrochloride (25.0 g, 0.130 mol) was added in one portion.The reaction mixture was stirred for 10 minutes and warmed to room temperature for 5 hours.The mixture was cooled to 0°C and quenched with saturated ammonium chloride solution.The resulted mixture was diluted with water and extracted (4x) with ethyl acetate, dried over anhydrous sodium sulfate and concentrated.The product was crystallized to afford 5 (24.4 g, 65%) as a white solid; 1