Selective C–H Olefination of Indolines (C5) and Tetrahydroquinolines (C6) by Pd/S,O-Ligand Catalysis

Abstract

Herein, we report a highly selective C–H olefination of directing-group-free indolines (C5) and tetrahydroquinolines (C6) by Pd/S,O-ligand catalysis. In the presence of the S,O-ligand, a wide range of challenging indolines, tetrahydroquinolines, and olefins was efficiently olefinated under mild reaction conditions. The synthetic potential of this methodology was demonstrated by the efficient olefination of several indoline-based natural products.

Indolines and tetrahydroquinolines (THQs) are ubiquitous structures in natural products and pharmaceuticals.¹ The development of new methodologies that permit the selective C–H functionalization of these structures could considerably widen the extent of current strategies for diversity-oriented synthesis in medicinal chemistry.² In this context, two main strategies to achieve efficient and selective C(sp²)–H functionalization reactions of indolines and THQs were employed. The first approach consists of the use of directing groups attached to the nitrogen atom, which leads to functionalized C7-indolines and C8-THQs (Figure 1a),³ while the second one provides C6-indolines and C7-THQs by using templates attached to the nitrogen atom (Figure 1b).⁴ In the particular case of indolines, the selective C5 functionalization was accomplished via (a) Ru(II)-catalyzed difluoromethylation,⁵ (b) Au(I)-catalyzed alkylation,⁶ and (c) Zn(II)-catalyzed Michael-type Friedel–Crafts alkylation (Figure 1c).⁷ In these examples, only alkyl groups are introduced, and the substrate scope is limited to neutral or electron-rich indolines. To the best of our knowledge, general strategies to selectively obtain C5-olefinated indolines and C6-olefinated THQs are still elusive.⁸ Herein, we report the first C5–H olefination of indolines and C6–H olefination of THQs by Pd/S,O-ligand catalysis (Figure 1d). The reaction in the presence of the S,O-ligand proceeds efficiently with a wide range of indolines, THQs, and olefins, providing the desired olefinated products with excellent selectivity and high yields.

Figure 1.

Metal-catalyzed selective C–H functionalization of indolines and THQs.

Recently, we found out that the C–H olefination of a variety of aromatic compounds can be promoted by the presence of bidentate S,O-ligands.⁹ In particular, we reported the first general para-selective C–H olefination of aromatic amines. Thus, we hypothesized that a selective C–H olefination of indolines and THQs, which are ubiquitous moieties in natural products, could be achieved in the presence of our Pd/S,O-ligand catalyst.

First, we evaluated the reactivity of different N-protected (Me, Bn, Boc) indolines under conditions similar to the ones used in the C–H olefination of anilines (see Supporting Information, Table S1).^9d We observed that N-methyl indoline (1a) provided the highest yield (38%) and C5 selectivity and that indolines were less reactive than anilines as well as more sensitive to higher temperatures. Thus, different temperatures, reaction times, and stoichiometries were tested to obtain a compromise between reactivity and stability. Finally, the reaction of N-methyl indoline (1a) (2 equiv) under the optimized reaction conditions (Scheme 1) provided the desired C5 olefinated product in 58% isolated yield and with excellent C5 selectivity (20 > 1). With the optimal reaction conditions in hand, we studied the substrate scope of a variety of N-methyl indolines.

Scheme 1. C5 C–H Olefination of N-Methyl Indolines.

Isolated yields. Selectivities were determined by ¹H NMR analysis of the crude mixture.

A mixture of DCE and HFB (1:4, v/v) was used as solvent.

The reaction was performed at 80 °C.

The reaction time was 8 h.

4.0 mmol scale.

A mixture of DCE and HFB (1:1, v/v) was used as the solvent.

1.0 equiv of indoline substrate and 2.0 equiv of ethyl acrylate were used.

First, we explored the reaction of N-methyl indolines bearing electron donating substituents (Me, OMe) in the aromatic ring. To our surprise, the olefinated indoline products were obtained in low yields (see Supporting Information, Table S8), in contrast to the reactivity observed when using N,N-dialkyl anilines.^9d,10 Then, we tested a variety of indolines bearing electron withdrawing substituents. The reaction of N-methyl 4-, 6-, and 7-fluoroindolines (1b–d) provided the desired C-5 olefinated products in good yields (76–51%) and perfect selectivities (20 > 1). The slightly lower yield obtained with 7-fluoroindoline (1d) can be explained by the deactivation ability of the fluorine atom at the meta position. The same trend was observed when chlorine-substituted substrates were used. The reaction of N-methyl 4-chloroindoline (1e) furnished the C5-olefinated product in 69% yield, while the N-methyl 7-chloroindoline olefinated product 2f was obtained in slightly lower yield (56%). Synthetically useful yield (54%) and good selectivity (20 > 1) were obtained in the reaction of the methyl 1-methylindoline-7-carboxylate (1g). Substrate 1h, which has a benzoyl group at the 7-position, delivered the olefinated product in 76% isolated yield with slightly lower C5-selectivity (15:1).

Next, we evaluated indolines substituted at C2 and/or C3 positions, which are scaffolds present in a wide range of natural products and pharmaceuticals.¹ The reaction of N-methyl 2-methylindoline (1i) provided the olefinated product in 54% yield and perfect C5-selectivity. Interestingly, when the methyl group is present at the C3 position instead of at C2 position, higher yield (76%) and lower C5-selectivity (14:1) was observed (2j, Scheme 1). Good yields (72–67%) and perfect selectivities were obtained using 3,3-dialkyl indolines 1k and 1l. The reaction of 2,3-indoline-fused cyclohexane 1m and cyclopentane 1n furnished the olefinated products in 48 and 71% yields, respectively, with perfect C5-selectivity. When the pyrroloindoline 1o skeleton that is found in many natural products and pharmaceuticals was used under standard reaction conditions, the olefinated pyrroloindoline 2o was obtained in 86% isolated yield and with excellent selectivity. The reaction of the furoindoline derivative 1p provided the C5-olefinated product in 62% isolated yield. Finally, the olefinated product 2q, obtained from the reaction of tetrahydro-9-pyridoindoline, was isolated in 71% yield with perfect selectivity. To prove the scalability of this transformation, we performed the reaction of 3,3-dimethyl indoline 1k on a 4.0 mmol scale, which provided the olefinated product 2k in 63 yield.

The crucial role of the S,O-ligand in the reaction was demonstrated by comparing the results of the reaction with and without the ligand (Scheme 1). In all cases, the presence of the S,O-ligand was key to obtain the olefinated products in good yield and excellent selectivity.

After demonstrating the efficiency of our catalytic system in promoting the C–H olefination of indolines, we investigated the olefination of tetrahydroquinolines (Scheme 2). The reaction of N-methyl THQ 3a under the optimal reaction conditions (for optimization of reaction conditions, see the Supporting Information, Tables S9–S11) provided the olefinated product 4a in 73% isolated yield with perfect selectivity. In contrast with the reactivity observed for indolines bearing methyl groups in the aromatic ring, N-methyl 5-methyl THQ 3b and N-methyl 7-methyl THQ 3c were olefinated in 50 and 54% yield, respectively. The reaction of N-methyl 2,2,4,7-tetramethyl THQ (3d) furnished the olefinated product in 62% isolated yield. Then, we performed the reactions of more electron poor THQs. Under optimal conditions, N-methyl 7-chloro THQ (3e) and N-methyl 2,3-dihydro-1H-quinolin-4-one (3f) were olefinated in 53 and 56% yield, respectively, and with excellent selectivity. Reactions with spirotetrahydroquinolines 3g and 3h provided the olefinated products in 73 and 71% yield. Finally, we tested the reaction of N-methyl 8-chloro THQ (3i). As expected, this substrate gave only a trace amount of olefinated product, in line with the reactivity observed with N,N-dimethyl ortho-substituted anilines.^9d Our previous DFT calculations proved that the lack of reactivity of ortho-substituent anilines is due to the twist of the nitrogen atom out of the plane, deactivating the aniline. To prove that the same situation occurred in this case, we performed the reaction of the unprotected 8-chloro THQ 3j, which provided the olefinated product in 32% isolated yield. Although the reaction was still not efficient, the higher yield obtained for the unprotected THQ in comparison with the protected one 3i confirms that the same situation occurred. Indeed, the reaction of the unprotected 8-etanone THQ (3k) furnished the olefinated product in 78% yield. Again, the key role of the S,O-ligand in the reaction was confirmed by comparing the results of the reaction with and without the ligand.

Scheme 2. C6 C–H Olefination of N-Methyl THQs.

Isolated yields. Selectivities were determined by ¹H NMR analysis of the crude mixture.

Reaction was performed at 50 °C.

1,4-Dioxane was used as the solvent.

Reaction was performed at 80 °C.

Next, we evaluated the scope of olefins, as shown in Scheme 3. The reaction of N-methyl 3,3-dimethyl indoline (1k) with several olefins, including methyl, phenyl, and cyclohexyl acrylates, furnished the olefinated products 5a–c in high yields (72–76%) and selectivities. α-Methylene-γ-butyrolactone afforded compound 5d in 79% yield as a mixture of 5d1, 5d2, and 5d3 in a ratio 6:12:1. Other activated olefins such as methyl vinyl ketone and vinylphosphonate were also used, providing the olefinated products 5e and 5f in 55 and 82% yields, respectively. We also tested the C–H olefination using the spirotetrahydroquinoline 3h. The reaction using vinyl amide and vinyl sulfonate provided the corresponding olefinated products 5g and 5h, respectively, in synthetically useful yields (51–68%). To our delight, the challenging substrate styrene was also a suitable olefin for this reaction, providing the olefinated product 5i in 51% yield.

Scheme 3. Scope of Olefins.

Reaction conditions: (A) 1k (0.5 mmol), olefin (0.25 mmol), Pd(OAc)₂ (10 mol %), S,O-ligand (10 mol %), PhCO₃^tBu (1.0 equiv) in DCE (1.25 mL) at 60 °C for 16 h; (B) 3h (0.25 mmol), olefin (0.375 mmol), Pd(OAc)₂ (10 mol %), S,O-ligand (10 mol %), PhCO₃^tBu (1.0 equiv) in DCE (1.25 mL) at 40 °C for 16 h. Isolated yields. Selectivities were determined by ¹H NMR analysis of the crude mixture.

In conclusion, we developed the first C5–H olefination of indolines and C6–H olefination of THQs by Pd/S,O-ligand catalysis. The reaction in the presence of the S,O-ligand proceeded efficiently with a wide range of indolines, THQs, and olefins, providing the desired olefinated products with excellent selectivity and high yields. Further applications and mechanistic studies are currently ongoing in our laboratory.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b03505.

• General information, synthesis of indoline and quinoline substrates, reaction optimization for the C5 C–H olefination of indolines, general procedure for Pd-catalyzed C5 C–H olefination of indolines, reaction optimization for the C6 C–H olefination of tetrahydroquinolines, general procedure for Pd-catalyzed C6 C–H olefination of tetrahydroquinolines, general procedure for the evaluation of olefins, large scale reaction of Pd-catalyzed C5 C–H olefination of 1,3,3-trimethylindoline, ¹H NMR, ¹³C NMR, and ³¹P NMR spectra (PDF)

The authors declare no competing financial interest.