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Iron-Catalyzed C(sp2)–C(sp3) Cross-Coupling of Aryl Chlorobenzoates with Alkyl Grignard Reagents

Aryl benzoates are compounds of high importance in organic synthesis. Herein, we report the iron-catalyzed C(sp2)–C(sp3) Kumada cross-coupling of aryl chlorobenzoates with alkyl Grignard reagents. The method is characterized by the use of environmentally benign and sustainable iron salts for cross-coupling in the catalytic system, employing benign urea ligands in the place of reprotoxic NMP (NMP = N-methyl-2-pyrrolidone). It is notable that high selectivity for the cross-coupling is achieved in the presence of hydrolytically-labile and prone to nucleophilic addition phenolic ester C(acyl)–O bonds. The reaction provides access to alkyl-functionalized aryl benzoates. The examination of various O-coordinating ligands demonstrates the high activity of urea ligands in promoting the cross-coupling versus nucleophilic addition to the ester C(acyl)–O bond. The method showcases the functional group tolerance of iron-catalyzed Kumada cross-couplings.

In this Special Issue on Recent Advances in Iron Catalysis, we detail our findings on the development of the iron-catalyzed cross-coupling of aryl chlorobenzoates with alkyl Grignard reagents (Scheme 1). The reaction is notable for several reasons: (1) the method allows for the synthesis of alkyl-functionalized aryl benzoates, which represent compounds of high importance in organic synthesis (Scheme 2); (2) the method demonstrates the exceptional functional group tolerance of the iron system, wherein the selective Kumada cross-coupling is achieved in the presence of the hydrolytically labile and prone to nucleophilic addition C(acyl)-O ester moiety. This model system is well suited for the examination of various O-coordinating ligands in promoting the cross-coupling versus nucleophilic addition to the
At the outset, we probed the model reaction between phenyl 4-chlorobenzoate (1a) and ethylmagnesium chloride in the presence of benign DMI (DMI = 1,3-dimethyl-2-imidazolidinone) ( Table 1). Under standard conditions, the cross-coupling proceeded in 27% yield with the remaining mass balance corresponding to the alcohol product (Table 1, entry 1). Lowering the equivalents of the Grignard reagent had no impact on the reaction efficiency (Table 1, entry 2). After experimentation, we found that the slow addition of the close to equimolar quantity of the Grignard reagent afforded the desired cross-coupling product in 65% yield (Table 1, entry 3). Interestingly, using an excess of DMI led to lower cross-coupling efficiency, which was likely due to facilitating the nucleophilic addition to the carbonyl group (Table 1, entry 4). DMI improves the coupling efficiency; however, this additive is not required, as demonstrated by the cross-coupling in its absence (Table 1, entries  3-6). Furthermore, using Grignard as the limiting reagent as well as extending the addition time had a deleterious effect on the cross-coupling (  [13][14], resulted in no cross-coupling with the alcohol formed as the sole reaction product, thereby highlighting the key role of iron to promote the cross-coupling. Finally, for comparison purposes, we tested NMP as the additive ( Table 1, entry 15). Interestingly, NMP resulted in lower cross-coupling efficiency than DMI (vide infra), highlighting the beneficial effect of this ligand beyond its favorable toxicological profile (cf. NMP). Then, we examined the scope of the optimized iron catalytic system as outlined in Table 2. We were pleased to find that neutral as well as electron-rich aryl 4-chlorobenzoates, such as 4-tert-butyl and 4-methoxy, enabled the chemoselective cross-coupling in good yields ( Table 2, entries 1-3). Furthermore, electron-deficient aryl 4-chlorobenzoates, such as 4-fluoro, are also tolerated, albeit the cross-coupling product is obtained in lower yield (Table 2, entry 4). As expected, the reactivity trend mirrors the electronic properties of the aryl ester in that electron-deficient aryl substituents increase O lp to Ar conjugation, leading to the lower yield in the cross-coupling. Pleasingly, we found that both sterically-hindered 2-methyl and 2,6-dimethyl aryl 4-chlorobenzoates are well-tolerated (Table 2, entries 5-6) and result in significantly improved yields for the cross-coupling as a result of steric shielding of the C(acyl)-O bond. Thus, we recommend that electron-rich or sterically hindered aryl benzoates are used for the cross-coupling to minimize the formation of the alcohol side products. 4-Chlorophenyl 4-chlorobenzoate is not a suitable substrate due to nucleophilic addition. The scope of Grignard reagents was also briefly examined (Table 2, entries 7-10). As such, longer primary alkyl Grignard reagents such as hexyl or tetradecyl gave the cross-coupling products in high yields (Table 2, entry 7-8). The cross-coupling of more sterically hindered secondary Grignard reagents is feasible; however, it leads to modest yield ( Table 2, entry 9). Finally, we were pleased to find that the challenging phenethyl Grignard reagent that is prone to β-hydride elimination is also a competent nucleophile for this cross-coupling protocol ( Table 2, entry 10), attesting to the efficiency of the cross-coupling. At present, cross-coupling of 3-substituted aryl chlorobenzoates is not feasible due to facile hydrolysis. Next, intermolecular competition studies were performed to gain insight into the selectivity of this cross-coupling (Scheme 3). (A) Competition experiments between phenyl and methyl ester (OPh:OMe = 2.5:1.0) revealed that aryl esters are more reactive than their alkyl counterparts, which is consistent with the facility of oxidative addition. (B) Similarly, competition between electron-rich and electron-deficient aryl esters (4-MeO:4-F = 1.0:1.25) revealed that electron-deficient arenes are more reactive. This observation is in agreement with the O-aryl ester activating the aromatic ring for the cross-coupling; however, its increased electrophilicity leads to a competing nucleophilic addition to give the alcohol products. The formation of the alcohol could be minimized by using sterically hindered or electron-rich aromatic esters. Finally, we have probed the effect of various additives on the cross-coupling (Table 3 and Figure 1). At present, one of the major challenges in iron-catalyzed C(sp 2 )-C(sp 3 ) cross-coupling is replacing the reprotoxic NMP by benign yet effective additives.

Entry
Fe (

Discussion
In summary, we have reported the iron-catalyzed C(sp 2 )-C(sp 3 ) Kumada cross-coupling of aryl chlorobenzoates with alkyl Grignard reagents. The iron-catalyzed cross-coupling reactions have gained significant momentum due to the beneficial environmental and sustainability profile compared to precious metals. However, what is equally important is the fact that iron catalysis enables cross-coupling reactions that are difficult or impossible to achieve with other metals, the prime example being the industrially-relevant C(sp 2 )-C(sp 3 ) Kumada cross-coupling. The present study expands the scope of benign iron-catalyzed cross-couplings with urea ligands as replacements for toxic NMP to embrace the functional group tolerance of highly reactive aryl benzoates without cleavage of the sensitive C(acyl)-O bond. Future studies will be focused on expanding the scope of iron-catalyzed cross-couplings and the design of new amide-based ligands for iron catalysis.

General Information
All compounds reported in the manuscript are commercially available or have been previously described in the literature unless indicated otherwise. All experiments involving iron were performed using standard Schlenk techniques under argon or nitrogen atmosphere unless stated otherwise. All esters have been prepared by standard methods [66]. All yields refer to yields determined by 1 H-NMR and/or GC/MS using an internal standard (optimization) and isolated yields (preparative runs) unless stated otherwise. 1 H-NMR and 13 C-NMR data are given for all compounds in the Experimental section for characterization purposes. 1 H-NMR, 13 C-NMR, and HRMS data are reported for all new compounds. All products have been previously reported, unless stated otherwise. Spectroscopic data matched literature values. General methods have been published [36][37][38][39][40][41][42][43]. All new compounds have been characterized by established guidelines by 1 H-NMR, 13 C-NMR, HRMS, and Mp as appropriate.

General Procedure for Iron-Catalyzed C(sp 2 )-C(sp 3 ) Cross-Coupling
An oven-dried vial equipped with a stir bar was charged with an ester substrate (neat, typically, 0.50 mmol, 1.0 equiv) and Fe(acac) 3 (typically, 5 mol%), which was placed under a positive pressure of argon and subjected to three evacuation/backfilling cycles under vacuum. Tetrahydrofuran (0.15 M) and ligand were sequentially added with vigorous stirring at room temperature, the reaction mixture was cooled to 0 • C, a solution of Grignard reagent (typically, 1.05 equiv) was added dropwise over 60 min with vigorous stirring, and the reaction mixture was stirred for the indicated time at 0 • C. After the indicated time, the reaction mixture was diluted with HCl (1.0 N, 1.0 mL) and Et 2 O (1 × 30 mL), and the organic layer was extracted with HCl (1.0 N, 2 × 10 mL), dried, and concentrated. The sample was analyzed by 1 H-NMR (CDCl 3 , 400 MHz) and GC-MS to obtain the conversion, yield and, selectivity using an internal standard and comparison with authentic samples. Purification by chromatography on silica gel afforded the title product.

General Procedure for Determination of Relative Reactivity
According to the general procedure, an oven-dried vial equipped with a stir bar was charged with two chloride substrates (each 0.50 mmol, 1.0 equiv) and Fe(acac) 3 (5 mol%), which was placed under a positive pressure of argon and subjected to three evacuation/backfilling cycles under vacuum. Tetrahydrofuran (0.15 M) and DMI (neat, 200 mol%) were sequentially added with vigorous stirring at room temperature, the reaction mixture was cooled to 0 • C, a solution of C 2 H 5 MgCl (2.0 M in THF, 0.25 mmol, 0.50 equiv) was added dropwise over 60 min with vigorous stirring, and the reaction mixture was stirred for 180 min at 0 • C. Following the standard work up, the sample was analyzed by 1 H-NMR (CDCl 3 , 400 MHz) and GC-MS to obtain the conversion, yield, and selectivity using an internal standard and comparison with authentic samples.