tmp₄Zr: An Atom‐Economical Base for the Metalation of Functionalized Arenes and Heteroarenes

Zirconium bases reach lots of places: Only 25 % of zirconium metal is required for the metalation of various functionalized aromatic compounds and heterocycles. All four 2,2,6,6-tetramethylpiperidyl (tmp) groups of the new base tmp4Zr⋅4 MgCl2⋅6 LiCl (1) are used up in the metalation process. The resulting zirconium species smoothly undergo palladium-catalyzed cross-couplings and addition to CO2 and epoxides (see scheme). The functionalization of aromatic and heterocyclic ring systems is of central importance in synthetic organic chemistry, beacuse polyfunctional unsaturated units are present in numerous pharmaceuticals and advanced materials.1 Directed metalation is a convenient method for performing such synthetic tasks. Whereas directed lithiations have been very popular,2 the recent development of kinetically highly active 2,2,6,6-tetramethylpiperidyl (tmp) bases3, 4 of various transition metals (Mn,5 Fe,6 and Ln7) that can be solubilized by complexation with lithium chloride allows a unique and simple preparation of polyfunctional Mn, Fe, or La unsaturated organometallic complexes. Early-transition-metal organometallic complexes have a particular reactivity pattern.8, 9 Especially, complexes derived from Ti and Zr are attractive due to their unusual reaction chemistry, the low cost of these metals, and their low toxicity.9 Herein, we report a new THF-soluble kinetically highly active zirconium base:10 tmp4Zr⋅4 MgCl2⋅6 LiCl (abbreviated as tmp4Zr (1)) which for the first time allows a direct zirconation of various functionalized aromatics and heterocycles of type 2 (scheme 1). Remarkably, this base is especially atom economical regarding the amount of transition-metal (0.25 equiv) and the use of tmp groups.11 All four tmp groups are used effectively in the metalation process allowing the preparation of a range of new, highly functionalized tetraorganozirconium derivatives of type 3 under mild reaction conditions (Scheme 1). Thus, the reaction of ethyl 3-fluorobenzoate (2 a, 1 equiv) with 1 (0.25 equiv) at 25 °C for 45 min provides the tetraarylzirconium reagent 3 a in over 95 % yield (as indicated by iodolysis or allylation of reaction aliquots). The zirconated reagent 3 a displays a remarkable reactivity. Its allylation with ethyl (2-bromomethyl)acrylate (1.05 equiv, CuCN⋅2 LiCl (5 mol %), 0 °C, 1 h) furnished the diester 5 a, isolated in 88 % yield (Scheme 2). The addition to benzaldehyde (1.05 equiv, 0 °C, 2 h) led to the lactone 5 b in 86 % yield. A direct palladium-catalyzed cross-coupling without further transmetalation12a using [Pd(PPh3)4] (3 mol %, 25 °C, 8 h) afforded the biphenyl derivative 5 c in 77 % yield. Styrene oxide was opened by the zirconium reagent 3 a at 50 °C within 1 h providing after workup the annelated lactone 5 d in 65 % yield. Interestingly, the new tetraarylzirconium species (3 a) reacts smoothly with CO2 (1 atm, 50 °C, 8 h) furnishing the corresponding acid 5 e, isolated in 84 % yield.12b,12c Similarly, a range of zirconated aromatic substrates undergo this carboxylation reaction as well leading to the polyfunctional benzoic acids (5 f–j) in 79–89 % yields (Scheme 2). Preparation of 1 and its reaction with aromatics or heterocycles of type 2. Preparation of tetraarylzirconium reagent 3 a using 1 and its reactivity with various electrophiles. A range of substituted benzoates were zirconated with 1 (0.25 equiv) at temperatures between −15 °C and 25 °C (see entries 1–10 of Table 1). The resulting zirconated aromatics 2 b–j react with various electrophiles. Thus, a copper(I)-catalyzed acylation12d with 2-chlorobenzoyl chloride (1.0 equiv, CuCN⋅2 LiCl (25 mol %), −20 °C, 1 h) gave the benzophenone 5 k in 82 % yield (entry 1 of Table 1). The addition of 2 b to cyclohexane carbaldehyde (1.0 equiv, 0 °C, 2 h) led to the lactone 5 l in 76 % yield (Table 1, entry 2). A palladium-catalyzed cross-coupling of the zirconated aromatics 2 c–e with various aryl iodides proceeded in each case directly without the need of an additional transmetalation, furnishing the functionalized biphenyls 5 m–o in 78–81 % yields (Table 1, entries 3–5). The stannylation of the tetraarylzirconium reagent derived from 2 f using Me3SnCl (1.0 equiv, 0 °C, 2 h) gave the arylstannane 5 p in 75 % yield (Table 1, entry 6). Whereas, the zirconation of 3-fluoroanisole (2 g) with 1 at 25 °C led to a substantial formation of benzyne,9d this decomposition pathway can be avoided by performing the zirconation of 2 g at −20 °C (0.25 equiv of 1, 3 h). Quenching of the resulting tetraarylzirconium compound with thiophene-2-carbonyl chloride (1.0 equiv, CuCN⋅ 2 LiCl (25 mol %), −20 °C, 1 h) led to the ketone 5 q in 83 % yield (Table 1, entry 7). The benzonitrile 2 h was metalated by 1 (0.25 equiv, 0 °C, 45 min) in position 2. A cross-coupling with 4-chloro-1-iodobenzene (0.8 equiv, 25 °C, 8 h) using [Pd(PPh3)4] (3 mol %) gave the biphenyl 5 r in 73 % yield (Table 1, entry 8). By treating the ester-substituted aromatic nitrile 2 i with 1 (0.25 equiv) at −15 °C for 1.5 h, a regioselective zirconation at the position ortho to the ester function led, after addition of 4-methoxybenzaldehyde, to the lactone 5 s in 79 % yield (Table 1, entry 9). A regioselective metalation with 1 (0.25 equiv, 0 °C, 45 min) was also observed for the bromoester 2 j leading to the biphenyl 5 t in 83 % yield after palladium-catalyzed cross-coupling with 4-trifluoromethyl-1-iodobenzene (0.9 equiv, 25 °C, 8 h; Table 1, entry 10). Sulfamates such as 2 k,l are also readily metalated in the position ortho to the sulfamate with 1. After copper-catalyzed acylation with various acid chlorides, the polyfunctional ketones 5 u,v were obtained in 79–80 % yields (Table 1, entries 11 and 12). Entry Substrate[a] Electrophile Product[b] Entry Substrate[a] Electrophile Product[b] 1 2 b (25, 0.45) 5 k: 82 %[c] 7 2 g (−20, 3) 5 q: 83 %[c] 2 2 b (25, 0.45) 5 l: 76 % 8 2 h (0, 0.75) 5 r: 73 %[d] 3 2 c (25, 0.30) 5 m: 79 %[d] 9 2 i (−15, 1.5) 5 s: 79 % 4 2 d (25, 2.5) 5 n: 78 %[d] 10 2 j (0, 0.75) 5 t: 83 %[d] 5 2 e (0, 2) 5 o: 81 %[d] 11 2 k (25, 2) 5 u: 79 %[c] 6 2 f (0, 2) 5 p: 75 % 12 2 l (25, 4) 5 v: 80 %[c] The functionalization of heterocycles is of key importance for the preparation of novel pharmaceuticals and agrochemicals.13a A range of heterocyclic structures could be zirconated using 1. Thus, chromone (2 m) reacted smoothly with 1 (0.25 equiv, −35 °C, 30 min) affording the expected zirconium derivative 3 m in approximately 90 % yield. Copper-catalyzed allylation12d with cinnamyl chloride (−40 °C, 1 h) provided the SN2-substitution product 6 a as a single regioisomer in 76 % yield (Scheme 3). Direct zirconation of various heterocycles with 1. The functionalization of electron-poor pyridines is especially challenging, because of the high tendency of such metalated pyridines to polymerize.13b,13c Also, the regioselective metalation of substituted pyridines can also be complicated.13d,13e Treatment of 3-bromopyridine (2 n) with 1 at −10 °C for 45 min provided a regioselective zirconation in position 2 leading to the tetrapyridylzirconium species 3 n. After a palladium-catalyzed cross-coupling with 4-trifluoromethyl-1-iodobenzene (50 °C, 8 h), the expected pyridine 6 b was obtained in 79 % yield. The sensitive 4-cyanopyridine (2 o) also reacted smoothly with 1 within 15 min at −40 °C furnishing regioselectivly the tetra(2-pyridyl)zirconium derivative 3 o which, after copper-catalyzed allylation with 3-bromocyclohexene, gave the 2,4-disubstituted pyridine 6 c in 80 % yield (Scheme 3). Recently, we have shown that BF3⋅OEt2 is compatible with the presence of strong Lewis bases, such as tmpMgCl⋅LiCl or tmp2Zn⋅2 MgCl2⋅2 LiCl.14 The Lewis pairs formed15 are reversibly cleaved in the presence of a substrate, such as a pyridine or a quinoline. The new tmp4Zr base 1 displays a similar behavior. Thus, the reaction of 6-methoxyquinoline (2 p) with a mixture of 1 (0.25 equiv) and BF3⋅OEt2 (1.05 equiv, 0 °C, 45 min) provides the mixed Zr–B species 3 p (Scheme 4). The formation of a 2-quinolyltrifluoroborate 3 p was confirmed by 13C-, 19F-, and 11B NMR spectroscopy (see the Supporting Information). Palladium(0)-catalyzed cross-coupling with ethyl 4-iodobenzoate furnished the 2-functionalized quinoline 6 d in 79 % yield. Also, the sensitive 3-carbethoxypyridine 2 q was converted at −78 °C (15 min) by the reaction with 1 (0.25 equiv) into the pyridyltrifluoroborate 3 q. After copper-catalyzed allylation, the 3,4-disubstituted pyridine 6 e is obtained in 87 % yield (Scheme 4). This direct formation of N-heteroaromatic trifluoroborate complements the well-established preparation of these boron intermediates as described by Molander and Canturk.16 A number of heterocycles, such as coumarin (2 r, Table 2, entry 1), 2-phenyl-1,3,4-oxadiazole (2 s, Table 2, entry 2), electron-deficient 3-substituted pyridines (2 n, 2 t, 2 u; Table 2, entries 3–6), quinoline (2 v, Table 2, entry 7), 3-bromoquinoline (2 w, Table 2, entry 8), and 2-methylthiopyrazine (2 x, Table 2, entry 9) could be zirconated either directly or in the presence of BF3⋅OEt2 (Table 2). The corresponding zirconated species efficiently reacted with various electrophiles, such as allylic halides, aryl iodides, or iodine, to give polyfunctional heterocycles in high yields (Table 2, entries 1–9). BF3-mediated metelation of N-heterocycles using tmp4Zr⋅4 BF3. Entry Substrate[a] Electrophile Product[b] 1 2 r (−40, 30) 6 f: 78 %[c] 2 2 s (0, 20) 6 g: 79 %[c] 3 2 t (0, 30) 6 h: 82 %[d] 4 2 u (−40, 15) 6 i: 83 %[c] 5 2 n (−78, 5) 6 j: 77 %[c,e] 6 2 t (−78, 7) 6 k: 79 %[c,e] 7 2 v (0, 30) 6 l: 83 %[c,e] 8 2 w (−20, 45) 6 m: 85 % 9 2 x (−35, 20) 6 n: 81 %[c] In summary, we have developed a directed zirconation of functionalized aromatic and heterocyclic compounds using the new base tmp4Zr⋅4 MgCl2⋅6 LiCl (1). In contrast to most other aryl organometallic complexes, the resulting aryl zirconated species display an excellent reactivity toward electrophiles, such as CO2 and epoxides. They undergo a smooth palladium-catalyzed cross-couplings (without further transmetalation) leading to a range of new polyfunctional unsaturated compounds. Further extension of the metalation capabilities of 1 are currently under investigation. Typical Procedure: Synthesis of 5 a: A dry argon-flushed 25 mL Schlenk-flask, equipped with a magnetic stirring bar and a septum, was charged with ethyl 3-fluorobenzoate (2 a; 336 mg, 2 mmol) in dry THF (2 mL). The tmp4Zr⋅4 MgCl2⋅6 LiCl (1, 0.5 M in THF, 4.2 mL, 2.05 mmol based on tmp) was added dropwise and the mixture was stirred at 25 °C for 45 min. The reaction mixture was cooled to 0 °C, then CuCN⋅2 LiCl (1 M in THF, 0.1 mL, 0.1 mmol) and ethyl 2-(bromomethyl)acrylate (400 mg, 2.1 mmol) were added and stirred for 1 h at 0 °C. The reaction mixture was quenched with a saturated aqueous NH4Cl solution (25 mL), extracted with diethyl ether (3×50 mL), and dried over anhydrous MgSO4. After filtration, the solvents were evaporated in vacuo. The crude product was purified by flash chromatography (silica gel; pentane/diethyl ether, 10:1) to give 5 a (449 mg, 88 %) as a colorless oil. Detailed facts of importance to specialist readers are published as ”Supporting Information”. 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