Catalytic enantioselective cyclization/cross-coupling with alkyl electrophiles.

As part of our ongoing effort to expand the scope of cross-coupling reactions of alkyl electrophiles, we have pursued a strategy wherein the nucleophilic coupling partner includes a pendant olefin; after transmetalation by such a substrate, if β-migratory insertion proceeds faster than direct cross-coupling, an additional carbon-carbon bond and stereocenter can be formed. With the aid of a nickel/diamine catalyst (both components are commercially available), we have established the viability of this approach for the catalytic asymmetric synthesis of 2,3-dihydrobenzofurans and indanes. Furthermore, we have applied this new method to the construction of the dihydrobenzofuran core of fasiglifam, as well as to a cross-coupling with a racemic alkyl electrophile; in the latter process, the chiral catalyst controls two stereocenters, one that is newly generated in a β-migratory insertion and one that begins as a mixture of enantiomers.

In recent years, significant progress has been reported on the development of methods for the transition-metal-catalyzed cross-coupling of alkyl electrophiles to generate carbon–carbon bonds, including enantioselective processes.[1] To date, most investigations of asymmetric catalysis have focused on stereoconvergent reactions of racemic secondary electrophiles,[2] although an advance has also been described with a racemic secondary nucleophile (top of Figure 1).[3]

Figure 1

Asymmetric cross-couplings of alkyl electrophiles.

As part of our ongoing effort to expand the scope of enantioselective cross-couplings of alkyl electrophiles, we are pursuing an approach wherein an organometallic reagent that bears a pendant olefin is employed as the nucleophilic coupling partner (bottom of Figure 1).[4−6] In the presence of a chiral catalyst, transmetalation and then β-migratory insertion (left side of Figure 2), followed by alkyl–alkyl coupling, could lead to the formation of two carbon–carbon bonds and a new stereocenter (bottom of Figure 1). This strategy complements asymmetric coupling processes wherein an intermediate of type A is generated through oxidative addition of an electrophile (right side of Figure 2).[7]

Figure 2

Complementary approaches to generating a precursor (A) for catalytic enantioselective cyclizations.

In this report, we establish that a transmetalation–insertion sequence can indeed be used to generate two, rather than one, carbon–carbon bonds in a cross-coupling with an alkyl electrophile and that this process can be achieved with good enantioselectivity. Specifically, we describe couplings of arylboron reagents that bear a pendant olefin with unactivated alkyl halides, thereby furnishing 2,3-dihydrobenzofurans[8,9] and indanes[10,11] in high ee (eq 1).

In order to enhance the likelihood of cyclization (β-migratory insertion) prior to coupling with the electrophile, we chose to focus on an organometallic coupling partner that could form a five-membered ring upon insertion, since such cyclizations are often facile. At the outset, it was unclear what catalyst would enable the desired sequence of bond-forming processes, much less achieve high enantioselectivity.

Interestingly, we have determined that a nickel/1,2-diamine-based catalyst, which we have found to be useful for enantioconvergent alkyl–alkyl couplings,[3,12] is also effective for the desired cyclization/cross-coupling sequence (Table 1, entry 1). Thus, in the presence of NiBr2·glyme and ligand 1, both of which are commercially available, the target 2,3-dihydrobenzofuran is generated in good ee and yield. Under these conditions, essentially none of the product of direct cross-coupling (without cyclization of the nucleophile) or of endo cyclization is observed (<5%).

Table 1

Catalytic Enantioselective Cyclization/Cross-Coupling with an Alkyl Electrophile: Influence of Reaction Parametersa

All data are the average of two experiments.

The yield was determined by GC analysis with the aid of a calibrated internal standard.

In the absence of NiBr2·glyme, ligand 1, or i-BuOH, the desired cyclization/cross-coupling product did not form in appreciable yield (Table 1, entries 2–4).[13] Furthermore, the use of a smaller excess of the arylboron reagent led to a somewhat lower ee and yield (entry 5).[14] Other ligands that we have found to be useful for enantioconvergent couplings of alkyl electrophiles were not effective for this new asymmetric cross-coupling with an alkyl halide (entries 6–8).[15] If the alkyl bromide was replaced with the corresponding alkyl chloride, essentially no 2,3-dihydrobenzofuran was observed (entry 9).[16]

We next examined the scope of this method for asymmetric cyclization/cross-coupling with alkyl bromides (Table 2).[17] A range of functionalized electrophiles serve as suitable reaction partners, furnishing the desired 2,3-dihydrobenzofuran in very good enantiomeric excess. A silane, an acetal, and an imide are compatible with the reaction conditions. The method is not limited to unhindered primary alkyl bromides; a β-branched primary and a secondary bromide also undergo cyclization/cross-coupling (entries 6 and 7).

Table 2

Catalytic Enantioselective Cyclization/Cross-Coupling with Alkyl Electrophilesa

All data are the average of two experiments.

Yield of purified product.

15% NiBr2·glyme and 17% ligand 1 were used.

Under similar conditions, indane derivatives can also be produced in high ee, although modest yield (eq 2).[17c] An attempt to generate a quaternary stereocenter furnished a promising initial result (eq 3).

A number of optically active 2,3-dihydrobenzofurans exhibit interesting biological activity,[8,9] including fasiglifam (Takeda Pharmaceuticals: TAK-875), which progressed to phase 3 clinical trials for type 2 diabetes until being withdrawn due to concerns about liver safety.[18] We have applied our method to a catalytic asymmetric synthesis of the dihydrobenzofuran core of fasiglifam (Scheme 1).

Scheme 1

Catalytic Asymmetric Synthesis of the 2,3-Dihydrobenzofuran Core of Fasiglifam

In view of the similarity of the optimized conditions for this new asymmetric cyclization/cross-coupling process to those for our stereoconvergent cross-coupling of racemic γ-haloamides,[12d] we investigated the possibility that a single chiral catalyst could accomplish two distinct enantioselective transformations: create a new stereocenter through the cyclization of an achiral nucleophile, as well as control the absolute stereochemistry of a second stereocenter through an enantioconvergent coupling of a racemic electrophile. As illustrated in eq 4, this objective can indeed be achieved (minor diastereomer: 86% ee).

In summary, we have expanded the scope of cross-coupling reactions of alkyl electrophiles by incorporating an olefin in the nucleophilic partner, which leads to the formation of an additional carbon–carbon bond and stereocenter, when compared with a simple cross-coupling. With the aid of a nickel/diamine catalyst (both components are commercially available), we have established that this strategy enables the synthesis of highly enantioenriched 2,3-dihydrobenzofurans and indanes through couplings with a range of alkyl halides. We have applied this new method to the generation of the dihydrobenzofuran core of fasiglifam, as well as to a transformation wherein the chiral catalyst controls the stereochemistry of two rather different processes: a β-migratory insertion and an enantioconvergent coupling of a racemic alkyl halide. Ongoing studies are directed at further enlarging the scope of cross-coupling reactions of alkyl electrophiles, as well as elucidating the mechanisms of these transformations.