Rhodium-Catalyzed Hydrofunctionalization: Enantioselective Coupling of Indolines and 1,3-Dienes

Abstract

We communicate a strategy for the hydrofunctionalization of 1,3-dienes via Rh-hydride catalysis. Conjugated dienes are coupled to nucleophiles to demonstrate the feasibility of novel C–C, C–O, C–S, and C–N bond forming processes. In the presence of a chiral JoSPOphos ligand, hydroamination generates chiral allylic amines with high regio- and enantioselectivity. Tuning both the pK_a and steric properties of an acid-additive is critical for enantiocontrol.

Graphical abstract

Conjugated dienes are raw materials for polymerization and attractive building blocks for medicinal and natural product synthesis.^1,2 Inventing enantioselective strategies for functionalizing dienes is an important challenge that has inspired Pd-catalyzed hydroamination,³ Co-catalyzed hydrovinylation,⁴ and Ru-catalyzed hydrohydroxyalkylation.⁵ To expand the power of hydrofunctionalization, we envisioned using Rh-hydride catalysis to couple 1,3dienes and nucleophiles (Figure 1).⁶ Iridium and rhodium-hydrides have been used to transform allenes and/or alkynes into electrophilic metal-π-allyl intermediates, which undergo nucleophilic attack to form branched products (Figure 1,A).⁷ Building on this strategy, our laborator y achieved the first enantioselective C–N and C–C bond forming reactions with alkynes.⁸ In analogy to allenes and alkynes, we reasoned that conjugate d dienes could be transformed via Rh-π-allyl intermediates to produce the corresponding 1,2- and/or 1,4-addition products (Figure 1,B). Herein, we report the generality of Rh-hydride catalysis for enabling atom-economic C–C, C–O, C–N, and C–S bond forming reactions with dienes. In addition, we demonstrate the first hydroamination of unsymmetric dienes with excellent regio- and enantiocontrol.⁹

Figure 1.

Rh-hydride catalyzed hydrofunctionalization of unsaturated compounds

The mechanism for our proposed hydrofunctionalization of dienes is depicted in Figure 2. It would be critical to identify the right combination of a rhodium catalyst and Brønsted acid (HX) to generate a Rh-hydride catalyst A capable of diene insertion. On the basis of steric preference, we reasoned that this Rh-hydride insertion would favor the terminal double bond to form Rh-π-allyl intermediate B. From this intermediate, there are two likely pathways for nucleophilic addition. One pathway (path a) involves anion exchange of B with nucleophiles to provide complex C. Reductive elimination of C releases 1,2-addition product D or 1,4-addition product E. Alternatively, the nucleophile can attack via an S_N2’ or S_N2 type step (path b) to generate product D or E.

Figure 2.

Reaction design for the hydrofunctionalization of 1,3-dienes

With this hypothesis in mind, we chose to investigate (E)-1-(4methoxyphenyl)-1,3-butadiene as the model substrate. We investigated a range of achiral bidentate phosphine ligands and acid additives. A summary of our most relevant findings is in Table 1. The 1,3-diene can be cross-coupled with various nucleophiles; promising yields were observed for C–C bond (51% yield), C–N bond (85% yield), C–O bond (37% yield), and C–S bond (61% yield) formations. In all cases, excellent regioselectivity for the 1,2-Markovnikov product was observed (>20:1 rr). Using acids with a wide pK_a range (2.3 to 6.8) was necessary to encompass nucleophiles such as diketones,¹⁰ indolines,^8a alcohols,¹¹ and thiophenols.¹² It appears that weaker nucleophiles performed better in the presence of stronger acid co-catalysts. With this promising reactivity established, we chose to optimize hydroamination due to the value of enantiopure amines in drug discovery.¹³

Table 1.

Constructing different C–X bonds via hydrofunctionalization of 1,3-diene^a

^aReaction conditions: NuH (0.2 mmol), 1,3-diene (0.3 mmol), [Rh(COD)Cl]₂ (2 mol%), ligand (4 mol%), acid (50 mol%), DCE (0.4 mL), 24 h. Isolated yields.

While there has been interest in enantioselective hydroamination of 1,3-dienes,¹⁴ most studies have focused on intramolecular variants.¹⁵ Prior to our study, Hartwig demonstrated the only example of an enantioselective, intermolecular hydroamination of 1,3-dienes; this study focused on cyclohexadiene.³ In contrast, enantioselective hydroamination of unsymmetric dienes had yet to be achieved. In considering this challenge, we chose indoline 1a and (E)-1-phenyl-1,3-butadiene 2a as model substrates (Table 2, A). Given our previous work on alkyne hydroamination,^8a our initial studies focused on using [Rh(COD)Cl]₂ as the precatalyst and m-xylylic acid A1 as the additive. Ligand (S,S)-BDPP L1, which gave high enantioselectivity for alkyne hydroamination, promoted diene hydroamination to form allylic amine 3aa in only 21% ee (17% yield, 12:1 rr). From an extensive ligand evaluation, we found the Josiphos ligand family L2–L4 gave excellent regioselectivity (>20:1 rr) but only modest reactivity and enantiocontrol. In comparison, the related JoSPOphos ligand L5¹⁶ afforded 3aa in 84% yield, 82% ee and >20:1 rr.

Table 2.

Ligand and acid effects on asymmetric hydroamination of 1,3-diene^a

^aReaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), [Rh(COD)Cl]₂ (2 mol%), ligand (4 mol%), acid (50 mol%), DCE (0.2 mL), 60 °C, 24 h. Yields determined by ¹H NMR using an internal standard. Regioselectivity determined by ¹H NMR analysis of the unpurified reaction mixture. Enantioselectivity determined by chiral SFC.

^bUsing [Rh(COD)OMe]₂ instead of [Rh(COD)Cl]₂.

With ligand L5 in hand, we next investigated the effect of the acid additive (Table 2, B). The structure and acidity of the carboxylic acid had a marked effect on both yields and enantioselectivities. As highlighted in Table 2, we found that the optimal acid additive was A4 (80% yield, 90% ee, >20:1 rr). In comparison, acids bearing less α-substitution, such as 2-phenylacetic acid A2 and 2,2-diphenylacetic acid A3, provided lower ee’s, 52% and 78%, respectively. On the other hand, bulky acids that were less acidic, such as A5 and A6, gave diminished yields (40% and 38%, respectively). These results show the significance of tuning both the pK_a and steric properties of the acid-additive in Rh-hydride catalysis. We anticipated that the carboxylate would undergo exchange more effectively with a methoxide versus chloride ligand.¹⁷ Thus, in an effort to further improve selectivity, we switched from using [Rh(COD)Cl]₂ to [Rh(COD)OMe]₂ and observed the desired product in 81% yield and 96% ee.

With this protocol, we explored the hydroamination of 1,3-diene 2a with various indolines 1 (Table 3). The substituent on the indoline had a negligible impact on the yield, regio- and enantioselectivity. In all cases, we observed excellent regioselectivity (>20:1 rr) for the Markovnikov 1,2-addition isomers in preference to the anti-Markovnikov 1,2-addition or 1,4-addition isomers. This type of regioselectivity was observed by Meek, although via π-acidic Rh-catalysis.^9h In addition, we obtained the allylic amines with high enantioselectivities (>94% ee). A slight decrease in enantioselectivity was observed with indolines containing electron-donating substituents at the 5-position (3ah, 81% yield, 88% ee) compared with other substituents. Together, these results represent the first intermolecular hydroamination of unsymmetric1,3-dienes with high regio- and enantiocontrol.⁹

Table 3.

Hydroamination using various indolines^a

^aReaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), [Rh(COD)OMe]₂ (2 mol%), JoSPOphos (4 mol%), Ph₃CCOOH (50 mol%), DCE (0.4 mL), 60 °C, 24 h. Isolated yields. Regioselectivity determined by ¹H NMR analysis of the unpurified reaction mixture. Enantioselectivity determined by chiral SFC.

Next, we studied the hydroamination of various 1,3-dienes 2 with indoline 1a (Table 4). Products bearing both electron-donating and electron-withdrawing groups on the phenyl ring were observed in high regio- and enantioselectivities. Due to steric effects, the coupling of indoline with ortho-substituted substrates 2j and 2k gave a slight decrease in yields (73% and 69%, respectively). This protocol tolerated a heterocycle substituted 1,3-dienes such as 2l (R = 2-furyl) and 2m (R = 2-thienyl) and afforded the corresponding allylic amines (R)-3la (78% yield, 95% ee) and (R)-3ma (73% yield, 92% ee). In addition, alkyl-substituted 1,3-diene 2n provided the product 3na in 68% yield, however the regioselectivity (6:1 rr) and enantioselectivity (76% ee) were lower compared to aryl substituted 1,3-dienes. For 1,3-pentadiene 2o, the desired product 3oa was obtained in 73% yield with 75% ee. We derivatized indoline 3oa via oxidation with DDQ to generate the corresponding indole 5,¹⁸ whose absolute configuration has been reported.¹⁹

Table 4.

Hydroamination of various 1,3-dienes^a

^aReaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), [Rh(COD)OMe]₂ (2 mol%), JoSPOphos (4 mol%), Ph₃CCOOH (50 mol%), DCE (0.4 mL), 60 °C, 24 h. Regioselectivity determined by ¹H NMR analysis of the unpurified reaction mixture. Isolated yields. Enantioselectivity determined by chiral SFC.

Hydrofunctionalization represents a promising way to transform dienes into enantiopure allylic motifs. Krische established the use of Ru- and Ir-hydrides to generate nucleophilic π-allyl species.^{5, 20} As a complementary approach, we developed Rh-hydride catalysts that transform dienes into electrophilic π-allyl species. By tuning the Rh-hydride’s structure and acidity, we achieved an enantioselective hydroamination for indolines and terminal dienes.²¹ Future studies will focus on understanding the origin of 1,2-addition vs. 1,4-addition. Moreover, we plan to design catalysts to expand scope and variants for enantioselective and regioselective C–C, C–N, C–O, and C–S bond formations.