A practical cobalt-catalyzed cross-coupling of benzylic zinc reagents with aryl and heteroaryl bromides or chlorides

Abstract

A catalytic system consisting of 5 mol% CoCl₂ and 10 mol% isoquinoline allows a convenient cross-coupling of benzylic zinc reagents with various aryl and heteroaryl bromides or chlorides leading to polyfunctionalized diaryl- and aryl-heteroaryl-methane derivatives.

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Pd-Catalyzed cross-couplings between organozinc reagents and various organic halides constitute a major C–C bond formation methodology (Negishi cross-coupling).¹ Due to the high price and toxicity of palladium, related transition metal-catalyzed cross-couplings involving zinc organometallics and Ni-, Fe- or Co-catalysts have been examined.^2–4 Furthermore, the use of zinc organometallics is of special synthetic interest due to the high functional group compatibility of zinc reagents.⁵ Recently, we have reported several preparation methods of benzylic zinc halides and demonstrated that these reagents undergo smooth Negishi cross-couplings.⁶ Also Bedford reported that benzylic halides undergo useful Fe-catalyzed cross-couplings with arylzinc reagents.⁷ Gosmini has shown in one-pot procedures that arylzinc reagents generated in situ via a cobalt-catalyzed zinc insertion undergo cross-couplings with benzyl chlorides.⁸ Interestingly, Ingleson has described a transition metal free cross-coupling between relatively non-functionalized diarylzincs with benzylic bromides and chlorides performed in the absence of coordinating ethereal solvents.⁹

Herein, we report a practical cobalt-catalyzed cross-coupling promoted by 10 mol% of isoquinoline between various benzylic zinc reagents with aryl and heteroaryl bromides or chlorides resulting in the formation of valuable diaryl- and arylheteroaryl-methane derivatives.¹⁰ Preliminary control experiments performed with benzylzinc chloride (1a; prepared via the oxidative insertion of magnesium turnings into benzyl chloride (2a) in the presence of LiCl and ZnCl₂)¹¹ and 4-bromo-benzonitrile (3a) in a 2 : 1 THF : MTBE mixture¹² (MTBE = methyl tert-butyl ether) show that in the absence of transition catalysts no reaction is observed at 50 °C in 2 h (Table 1, entries 1 and 2). Also, Fe-catalysts such as Fe(acac)₃, Fe(acac)₂ or FeCl₂ were inefficient (Table 1, entries 3–5).¹³ However, the use of 5 mol% CoBr₂, Co(acac)₂ and CoCl₂ show the formation of the desired cross-coupling product (4a) in 47–76% GC-yield (Table 1, entries 6–8).¹⁴

Table 1 Screening of catalysts for the palladium-free cross-coupling of benzylzinc chloride (1a) with 4-bromobenzonitrile (3a)

Entry	Catalyst (mol%)	Additive (mol%)	Yield^a^,^b
a 1.1 equiv. of benzylzinc chloride (1a) was used. b Determined by GC-analysis with tetradecane as an internal standard. c Isolated yield of pure product. d CoCl2 with a purity of 99.999% was used.
1	None	None	0
2	None	Isoquinoline (10)	0
3	Fe(acac)3 (5)	None	0
4	Fe(acac)2 (5)	None	Traces
5	FeCl2 (5)	None	Traces
6	CoBr2 (5)	None	47
7	Co(acac)2 (5)	None	70
8	CoCl2 (5)	None	76
9	CoCl2 (5)	4-Fluorostyrene (10)	66
10	CoCl2 (5)	TMEDA (10)	68
11	CoCl2 (5)	Isoquinoline (10)	87 (82)^c (72)^d
12	CoCl2 (5)	Isoquinoline (5)	75
13	CoCl2·2LiCl (5)	Isoquinoline (10)	69
14	CoCl2·2LiCl (5)	None	65

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Previously reported additives like 4-fluorostyrene,¹⁵ TMEDA¹⁶ or isoquinoline¹⁷ indicate a very positive effect of 10 mol% isoquinoline¹⁸ leading to an isolated yield of 82% for 4a (Table 1, entry 11; compared with entries 9 and 10). Decreasing the amount of isoquinoline to 5 mol% reduces somewhat the yield of 4a (Table 1, entry 12). Also, we found that the use of CoCl₂·2LiCl¹⁹ was not advantageous (Table 1, entries 13 and 14). Additionally, we have examined the influence of the commercial origin of CoCl₂ as well as its purity. Thus, CoCl₂ having a purity of 99.999% provides under the same conditions (50 °C, 2 h) the diarylmethane 4a in 72% yield (compared to 82%; see Table 1, entry 11).^20,21 The addition of MTBE as a cosolvent usually decreases the amount of homo-coupling and therefore enhances the product yield. However, large amounts of MTBE reduce the reaction rate. We found the solvent mixture THF : MTBE 2 : 1 to be optimal.²² Concerning the need of isoquinoline as ligand, an extensive screening showed that N-heterocycles behave best, whereas various phosphines did not promote the cross-coupling.²³

With these optimized conditions in hand, we studied the reaction scope of the cross-coupling between various benzylic zinc chlorides (1a–i) with a broad range of aryl and heteroaryl bromides or chlorides. First, the treatment of benzylic zinc reagents (1a,b) in the presence of 5 mol% CoCl₂ and 10 mol% isoquinoline with 4-bromobenzonitrile (3a) at 50 °C within 2 to 4 h is leading to the diarylmethane derivatives 4a,b in 77–82% (Table 2, entries 1 and 2). Furthermore, the cross-coupling of an ortho-substituted benzylzinc chloride (1c) with 3a afforded the desired arene (4c) in 74% yield (Table 2, entry 3). Similarly, the two functionalized benzylic zinc reagents (1d,e) cross-coupled with 3a giving the products 4d,e in 70–79% (Table 2, entries 4 and 5). The ester-substituted benzylzinc chloride (1f) underwent a smooth cross-coupling with 3a leading to the functionalized diaryl-methane 4f in 62% yield (Table 2, entry 6). Additionally, the cross-couplings of the more electron-donating benzylic zinc reagents (1g,h) with 4-bromo-benzonitrile (3a) furnished the arenes 4g,h in 65–82% yield (Table 2, entries 7 and 8).

Table 2 Isoquinoline-promoted Co-catalyzed cross-coupling of benzylic zinc reagents (1a–h) with 4-bromobenzonitrile (3a)

Entry	Benzylic zinc reagent^a	Electrophile	Product, yield^b^,^c
a 1.3–1.5 equiv. of benzylic zinc reagent were used. b Isolated yield of pure product. c Less than 15% of homo-coupling of the zinc reagent was observed.
1
2		3a
3		3a
4		3a
5		3a
6		3a
7		3a
8		3a

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The reaction scope of this cross-coupling proved to be quite broad. Thus, 2-bromo-benzophenone (3b) underwent the cobalt-catalyzed cross-coupling with the benzylzinc chloride (1b) yielding to the corresponding ketone 5a in 64% yield (Table 3, entry 1). Similarly, the coupling of ethyl 4-bromo-benzoate (3c) with the two benzylic zinc reagents (1e,g) led to the functionalized diarylmethane derivatives (5b,c) in 54–70% yield (Table 3, entries 2 and 3). Remarkably, 2-chloropyridines react well with various benzylic zinc reagents (Table 3, entries 4–9). The cross-couplings of the benzylzinc chlorides (1b,e) with ethyl 2-chloronicotinate (3d) proceeded smoothly under these conditions affording the 2,3-disubstituted pyridines (5d,e) in 60–95% yield (Table 3, entries 4 and 5). Also, 3-(ethoxycarbonyl)benzyl-zinc chloride (1f) underwent the coupling with the 2,3-di-substituted pyridine (3d) giving the functionalized aryl-hetero-arylmethane 5f in 68% yield (Table 3, entry 6). Furthermore, the cross-couplings of the benzylic zinc reagents (1d,g,i) with 2-chloro-nicotinonitrile (3e) led to the desired benzylated pyridines (5g–i) in 67–77% yield (Table 3, entries 7–9). Finally, the reaction of 3-fluorobenzylzinc chloride (1d) with ethyl 5-bromofuran-2-carboxylate (3f) afforded within 3 h the 2,5-disubstituted furan (5j) in 60% yield (Table 3, entry 10). The use of aryl bromides bearing electron-donating substituents led to low yields.²⁴

Table 3 Co-Catalyzed cross-coupling reactions of benzylic zinc reagents with aryl and heteroaryl halides

Entry	Benzylic zinc reagent^a	Electrophile	Product, yield^b^,^c
a 1.3–1.5 equiv. of benzylic zinc reagent were used. b Isolated yield of pure product. c Less than 15% of homo-coupling of the zinc reagent was observed.
1
2
3		3c
4
5		3d
6		3d
7
8		3e
9		3e
10

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Moreover, such benzylic zinc reagents undergo high yield cross-couplings with various chloro- or bromo-N-heterocycles. Thus, the reaction of 4-methoxybenzylzinc chloride (1g) with 2-bromopyrimidine (3g) and the two substituted pyridines, 2-chloro-5-(trifluoromethyl)pyridine (3h) and 2-chloro-6-fluoro-pyridine (3i), led rapidly (within 2 h) to the functionalized aryl-heteroarylmethanes (6a–c) in 52–83% yield (Scheme 1).

Scheme 1 Isoquinoline-promoted cross-coupling of the benzylic zinc reagent 1g with selected N-heterocycles (3g–i).

In summary, we have reported a new practical Co-catalyzed, isoquinoline-promoted cross-coupling of various benzylic zinc chlorides with a range of aryl and heteroaryl bromides and chlorides, producing polyfunctionalized diaryl- or arylhetero-aryl-methane derivatives. This method tolerates a variety of functional groups, such as esters, nitriles or ketones, and proceeds smoothly at 50 °C within 1–18 h. Remarkably, the combination of MTBE (MTBE = methyl tert-butyl ether) as co-solvent and isoquinoline as additive led only to small amounts of homo-coupling. In most cases, shorter reaction times and improved yields could be obtained. Further investigations towards the synthesis and applications of benzylic organo-metallics are underway in our laboratories.

We would like to thank the DFG for financial support. We also thank BASF SE (Ludwigshafen, Germany) and Rockwood Lithium GmbH for the generous gift of chemicals.

Notes and references

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18. We observed that 2,2′-bipyridine is also a satisfactory ligand for such cross-couplings.
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21. The obtained yield difference using the high purity CoCl₂ (99.999%) instead of the commercial CoCl₂ (≥97%, Sigma Aldrich) is attributed to the difference of solubility of these two salts. The CoCl₂ with the highest purity is significantly less soluble than the 97% pure CoCl₂. In fact, this control reaction was performed in only THF.
22. For a corresponding solvent screening, see: ESI,† Table S1.
23. For an extensive ligand screening, see: ESI,† Table S2.
24. Mechanistic studies are underway to explain these phenomena.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5cc10272c

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