Electrophilic Amide Allylation of 3‐Heterosubstituted Oxindoles: A Route to Spirocyclic 2‐Oxindoles Containing the α‐Methylene‐γ‐butyrolactam Structure

Abstract

This article reports a new route to access spirocyclic 2‐oxindoles containing the α‐methylene‐γ‐butyrolactam structure via “electrophilic amide allylation”. The key reaction was accomplished by using acetoxy methacrylamides and tetrakis(triphenylphosphine)palladium as catalyst, affording a variety of the amide allylated products in excellent yields. The successful cyclization of these products has demonstrated the potential utility of this approach to offer a practical synthesis of spirocyclic oxindoles.

The Allylic Acetoxylation of 1,1-Disubstituted Alkenes Catalyzed by a Palladium(II)/Monothiadiazole Ligand System

“…1 H NMR (400 MHz, CDCl3)δ2.18 (s, 3H), 4.98 (s, 2H), 5.81 (s, 1H), 6.20 (s, 1H), 7.18 (t, J = 7.4 Hz, 1H),7.39 (t, J = 7.8 Hz, 2H), 7.62 (d, J = 7.9 Hz, 2H). 13 C NMR(101 MHz, CDCl3)δ 171.0, 164.0, 142.4, 139.9, 137.7, 129.1, 124.6, 120.0, 63.3, 20.9.ESI-MS: C12H13NO3[M+H] + : 220.1;[M+Na] + :242.1;Spectral datamatchespreviouslyreporteddata 16. 2-((4-fluorophenyl)carbamoyl)allyl acetate (2g)This reaction was performedaccording to the general procedure for Pd(OAc)2 using N-(4-fluorophenyl)methacrylamide (179 mg, 1.00mmol).…”

Bifurcated synthesis of methylene-lactone- and methylene-lactam-fused spirolactams via electrophilic amide allylation of γ-phenylthio-functionalized γ-lactams

“…We initially chose N-phenyl-3-(acetoxy)isoindolinone (2a) as a reactant. However, 2a showed no reactivity under the reaction conditions determined for the palladium-catalyzed allylation in our previous work and was recovered in 98% yield [17] ( Table 1, entry 1). The use of strong bases such as potassium tert-butoxide or sodium hydride resulted in no formation of the desired product 3a because 2a was decomposed under the harsh reaction conditions ( Table 1, entries 2 and 3).…”

“…Meanwhile, we also developed an umpolung electrophilic allylation of 3-heterosubstituted oxindole D for the synthesis of lactam analog of A (Scheme 1c) [17]. The oxindole D readily reacted with 2-(acetoxy)methyl acrylamides 1 in the presence of a catalytic amount of Pd(PPh 3 ) 4 to give the corresponding adducts which could be delivered into an methylene-lactamfused oxindole.…”

Divergent Synthesis of Methylene Lactone- and Methylene Lactam-Based Spiro Compounds: Utility of Amido-Functionalized γ-Hydroxylactam as a Precursor for Cytotoxic N,O- and N,N-Spiro Compounds

“…In parallel with the development of acidic spirocyclization, an alternative route to 4 was investigated (method B in Figure ). In view of our previous success in the transformation of γ-hydroxy amides to γ-lactams, we anticipated that exposure of 3 to the conditions of Boc protection [Boc 2 O and 4-dimethylaminopyridine (DMAP)] would provide 4 via spontaneous lactone cyclization. However, in fact, the desired domino process did not take place, probably due to the poor nucleophilicity of the hydroxy group.…”