Rhodium(III)-Catalyzed C–H Activation Mediated Synthesis of Isoquinolones from Amides and Cyclopropenes

Abstract

We have developed a synthesis of 4-substituted isoquinolones from the Rh(III)-catalyzed, C–H activation mediated, coupling of O-pivaloyl benzhydroxamic acids and 3,3-disubstituted cyclopropenes. Experiments suggest the formation of a [4.1.0] bicyclic-system, which can open under acidic conditions to generate the desired isoquinolone.

Isoquinolones are a ubiquitous motif found in numerous medicinally interesting targets.¹ An approach to access this core is the Rh(III)-catalyzed coupling of amides with alkynes to provide 3,4-disubstituted isoquinolones.² Early reports by our group^2c and others^2b,d found that terminal alkynes were incompatible with the oxidative reaction conditions because of unwanted Glaser-type couplings. In contrast, when an internal oxidant is utilized, terminal alkynes can be used to provide 3-substituted isoquinolones in excellent yield.^2e Glorius expanded on this work by using MIDA-boronate terminal alkynes to access 3-MIDA boronate-substituted isoquinolones.^2f Absent from these reports is the ability to access 4-substituted isoquinolones (Figure 1).

Figure 1.

Proposed approach to access mono-substituted isoquinolones

We imagined this substitution pattern could be accessed through formation of an intermediate donor–acceptor cyclopropane.³ We were intrigued by some recent reports on the use of nitrogen donors on activated cyclopropanes.⁴ We speculated that 3,3-disubstituted-cyclopropenes could be coupled to benzhydroxamic acids to generate a [4.1.0] bi-cyclic heterocycle. In the presence of either a carboxylic acid or the Lewis acidic Rh(III) catalyst, the resultant cyclopropane could be opened to generate a 4-substituted isoquinolone (Figure 1). In contrast to previous examples which used alkynylation to achieve isoquinolones, our approach requires an alkenylation. This reactivity has previously been reported independently by Fagnou^2e and Glorius,⁵ and further developed by Rovis and Ward,⁶ Cramer,⁷ and Molander.⁸

Equation 1

We were pleased to find that O-pivaloyl benzhydroxamic acid 1a could be coupled to activated cyclopropene 2a in MeOH with CsOAc (200 mol %) and [RhCp*Cl₂]₂ (1 mol %) to provide the desired 3-substituted isoquinolone 3a in excellent yield (99%) (Equation 1).

The reaction scope is illustrated in Table 1. A variety of para-substituents are tolerated providing product in excellent yield (Table 1, 3b-3e, 3h). Substitution at the meta-position provides variable levels of selectivity. Methyl substituted starting materials offer product in >10:1 regioselectivity in the C–H activation, favoring activation distal to the substituent (Table 1, 3f). In contrast, methoxy-substituents provide product, but at a 1.1:1 mixture of regioisomers (Table 1, 3g). Highly electron rich gallic acid derivatives provide product in excellent yield (Table 1, 3i). Finally, when di-ethyl malonate based cyclopropene is used, the desired product is isolated in exquisite yield without transesterification.

Table 1.

Isoquinolone Scope^a

^aReaction conditions: Amides (1 equiv), cyclopropene (1.1 equiv), [RhCp*Cl₂]₂ (1 mol %), CsOAc (200 mol %), MeOH (0.2 M), 23 °C, 8 hours.

^bProduct provided as a 1.1:1 ratio of C-H activation regioisomers.

Unfortunately, our attempts to increase the scope of the cyclopropene component to include simple mono-activated cyclopropenes failed to provide the desired 4-substituted isoquinolone. We were, however, able to isolate the [4.1.0] bicyclic intermediate in 60% yield as a 1.4:1 ratio of inseparable diastereomers (Scheme 1).

Disappointed that the cyclopropane did not open under the reaction conditions, we sought an alternative method to open the donor-acceptor cyclopropane. When cyclopropanes 4a and 4b were submitted to a 2:1 mixture of 4M HCl in 1,4 dioxane/DCM and heated to 60 °C for 2 hours, the desired isoquinolone 5 was furnished in 95% yield (Scheme 2).

Based on these experiments, we propose that a Rh(III) catalyzed olefination occurs as described by Fagnou and Glorius to afford the [4.1.0] bi-cycle. We suggest that pivalic acid or [RhCp*Cl₂]₂, acting as a Lewis acid, catalyzes the opening of the donor acceptor cyclopropane to generate an acyl-imine, which tautomerizes to form the desired isoquinolone. In the absence of two activating groups, a stronger acid is required to achieve opening.

In conclusion, we have discovered a method to access 4-substituted isoquinolones from cyclopropenes and amides under Rh(III) catalysis. Isolation of a [4.1.0] bicycle supports the mechanism occurs in two discrete steps.

Scheme 1.

mono-activated cyclopropenes

Scheme 2.

Cyclopropane Opening