Synthesis of Spiroindenyl-2-Oxindoles through Palladium-Catalyzed Spirocyclization of 2-Bromoarylamides and Vinyl Bromides

An expeditious approach to the construction of spiroindenyl-2-oxindoles was developed via a palladium-catalyzed spirocyclization reaction of 2-bromoarylamides with vinyl bromides. The reaction formed spiropalladacycles as the intermediates via carbopalladation and the C–H functionalization of 2-bromoarylamides. The spiropalladacycles reacted with vinyl bromides to form spiroindenyl-2-oxindoles. A Heck process rather than vinylic C–H functionalization was involved in the reaction.


Optimization of the Reaction Conditions
Herein, we report a new approach for the synthesis of spiroindenyl-2-oxindoles through domino Heck/C-H functionalization reactions. This work was inspired by the reaction of C(sp 2 ), C(sp 3 )-palladacycle derived from ortho-iodomethoxybenzenes with vinyl bromides [56]. It should be mentioned that the reactions of 2-iodobiphenyls with vinyl bro-mides have also been reported [57,58]. The reactions also proceeded via C,C-palladacycle intermediates, which were captured by vinyl bromides to form 9-fluorenylidene products.
The research was commenced by investigating the reaction of model substrates acrylamide (1a) and 1-bromoprop-1-ene (2a) ( Table 1). After an extensive condition survey, spiroindenyl-2-oxindoles 3aa was generated in a yield of 74% under the reaction conditions shown in entry 1. The optimal yield was obtained by using 18-crown-6, which promoted the reaction perhaps by enhancing the solubility of K 2 CO 3 in THF (entry 2). Ligand s-phos played a crucial role in the reaction since its absence led to a very low yield and other phosphine ligands gave lower yields (entries 3-7). K 2 CO 3 was an essential base, and only a trace amount of the product was observed when other bases such as Na 2 CO 3 and KOAc were used (entries 8 and 9). Although 3aa was also formed when the reaction was carried out in other solvents, the yields were much lower (entries 10-12).

Substrate Scope for Acrylamides
Having developed an approach for the synthesis of spiroindenyl-2-oxindoles, we then probed its substrate scope (Scheme 1). We first examined the performance of acrylamides bearing different functionalities on the bromophenyl groups. The acrylamides containing an electron-donating methyl or electron-withdrawing cyano group underwent the cascade reaction (3ba and 3ca). Fluoro, chloro, and even bromo groups were well tolerated, and the corresponding spiroindenyl-2-oxindoles were formed in moderate yields (3da-3fa). The substituents on the other positions of the bromophenyl groups were also suitable (3ga-3ia). Furthermore, substrates bearing a substituent on the phenyl groups linked to the double bonds could also be transformed into spiroindenyl-2-oxindole products (3ja-3la). The structure of 3ja was confirmed by single crystal X-ray crystallography. Scheme 1. Acrylamide scope. All the reactions were carried out in a Schlenk tube in the presence of 1a (0.2 mmol), 2a (0.8 mmol), Pd(OAc) 2 (10 mol%), s-phos (10 mol%), 18-crown-6 (2.0 equiv), K 2 CO 3 (6.0 equiv), and THF (2.0 mL) at 100 • C for 24 h under N 2 .
Next, the reactions of acrylamide bearing different N-substituents were probed. A range of N-substituents, including the ethyl, benzyl 2-ethoxy-2-oxoethyl and 2-methylallyl group, were compatible, and a variety of spiroindenyl-2-oxindole derivatives were afforded (3ma-3qa). Finally, it should be noted that the substrate containing an ether linkage could also form the desired spirocyclic product 3ra (Scheme 2).

Substrate Scope for Vinyl Bromides
The vinyl bromide scope was then explored (Scheme 3). When styryl bromide was allowed to react with 1a under the slightly modified standard conditions, spiroindenyl-2oxindole 3ab and compound 3ab-I were obtained. The formation of 3ab-I should be due to the stabilization of the exocyclic double bond by the phenyl group. As expected, styryl bromide derivatives, such as trimethoxystyryl bromide and (E)-1-(2-bromovinyl)naphthalene, also gave two isomers (3ac and 3ac-I). The structure of 3ac-I was confirmed by singlecrystal X-ray crystallography. It should be noted that the trimethoxyphenyl group was on the same side as the benzene ring, and the double bond in compound 3ac-I had Zconfiguration. This structure provides crucial evidence regarding the mechanism of the reaction. (E)-2-(2-bromovinyl)thiophene was also reactive, and only the exocyclic double bond product (3ae-I) was obtained. Intriguingly, two products (3af and 3af-I) were also obtained in the reaction of alkylvinyl bromide 2f. The structure of 3af was also confirmed by single-crystal X-ray crystallography.

Mechanistic Studies
On the basis of the formation of the products and the previous reports [52,[56][57][58], a tentative mechanism was proposed as shown in Scheme 4. The catalytic cycle starts with the oxidative addition of substrate 1 to Pd 0 to form Pd II species A, which is followed by intramolecular migratory insertion to give alkylPd II species B. The subsequent intramolecular C-H functionalization affords palladacycle C. C undergoes oxidative addition with 2-bromoalkenyl derivatives to form Pd IV species D. The reductive elimination of D yields intermediate E. At this stage, E may undergo two pathways to form final product 3. Path I involves intermediate 3-I, which is formed through intramolecular migratory insertion and subsequent β-H elimination. Alternatively, the alkylPd II species of E may cleave the vinyl C-H bond to yield palladacycle G. G forms product 3-I-I and Pd 0 by reductive elimination (path II). Both 3-I and 3-I-I can isomerize to yield final product 3. It is challenging to distinguish these two pathways. Fortunately, the mechanism can be deciphered based on the structure of intermediate 3ac-I. If the reaction undergoes path II, 3-I-I, which has E-configuration, should be formed. On the contrary, compound 3-I with Z-configuration should be generated for path I. The Z-configuration of 3ac-I indicates that the reaction proceeds via path I. Scheme 4. Proposed mechanism.

General Information
Pd(OAc) 2 was purchased from Strem Chemicals (Newburyport, MA, USA). The 1H NMR and 13 C NMR spectra were recorded on a Bruker ARX400 instrument (400 MHz) or a Bruker DRX-600 instrument (600 MHz). High-resolution mass spectra were measured on a Bruker MicroTOF II ESI-TOF mass spectrometer. NMR spectra were recorded in CDCl 3 . The 1H NMR spectra were referenced to residual CHCl 3 at 7.26 ppm, and 13 C NMR spectra were referenced to the central peak of CDCl 3 at 77.0 ppm. Chemical shifts (δ) are reported in ppm and coupling constants (J) are in Hertz (Hz). Multiplicities are reported using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet.

Conclusions
In summary, we developed a palladium-catalyzed spirocyclization reaction between 2-bromoarylamides and vinyl bromides via a cascade Heck/C-H functionalization process. The reaction forms spiropalladacycles as the intermediate by carbopalladation and C-H functionalization of 2-bromoarylamides. The resulting spiropalladacycles react with vinyl bromides effectively and spiroindenyl-2-oxindoles are formed as the final products. The Z-configuration of the precursor was identified, and it indicates that a Heck process instead of a vinylic C-H functionalization is involved in the reaction. This reaction provides a novel and effective strategy for the construction of spiroindenyl-2-oxindoles.
Supplementary Materials: The following are available online. Synthetic procedure of starting materials, procedure and spectral data of products, copies of 1 H-NMR, 13 C-NMR spectra.

Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.

Data Availability Statement:
The data presented in this study are available on request from the corresponding author.