A comprehensive study of the effects of spectator ligands, transition metals and lithium halide additives on the efficiency of iron, nickel and palladium-catalyzed cross-coupling reactions of cyclohexyl magnesium bromide with fluorinated bromobenzenes

Thirteen mono-, bis-and trifluorinated bromobenzene derivatives have been coupled with cyclohexyl magnesium bromide or the corresponding lithiumchloride or lithiumbromide adducts. Iron, nickel and palladium complexes of the general formula [MCl 2 (dppx)] (x = (CH 2 ) n , n = 1, 2, 3) have been used as the precatalysts. Palladium based catalysts give high yields of the coupling product with the Grignard reagent itself whereas lithium halides are needed as additives to achieve comparable efficiencies if nickel and iron catalysts are used. Yields also depend on the chain length of the bridging units and on the fact whether fluorine substituents are present in ortho position with respect to bromine.


Introduction
Transition metal-catalyzed cross-coupling reactions have been shown to be an invaluable tool in terms of C-C bond formations.Most commonly organic halides are coupled with various nucleophiles like boronic acid derivatives, tin or zinc or lithium organic compounds or Grignard reagents. 1,2Besides to the use of palladium and nickel a number of iron and even vanadium catalyzed variations of these reactions have been reported.  To e best of our knowledge all reported iron catalyzed cross coupling reactions related to our work describe the coupling of an aryl Grignard reagent with an alkyl halide.We became interested in this field in connection with the search for efficient synthetic protocols for the cross coupling of cyclohexyl magnesium bromide with various fluorinated bromo benzene derivatives as electrophiles.The resulting cyclohexylbenzene derivatives and related compounds are widely used as liquid crystalline materials or as precursors in the synthesis of those.[44][45][46][47][48][49][50] Up to now they are mainly produced by cross-coupling reactions of the Suzuki type.[51][52][53] Nevertheless, this reaction protocol exhibits some major intrinsic disadvantages.First of all, the corresponding boronic acid esters have to be purchased or synthesized.Moreover, stoichiometric amounts of a base have to be applied and there are quite substantial amounts of waste.On the other hand, cross-coupling reactions involving Grignard reagents have to be performed under inert conditions and ideally concentrations of Grignard solutions have to be determined by titration before the coupling reaction itself.Of course solutions of Grignard reagents also have to be purchased or synthesized.Nevertheless, in most cases they will be cheaper compared to boronic acid esters.If Grignard reagents are to be used as nucleophiles in coupling reactions with aryl bromides or chlorides it has been shown that lithium halide adducts of the Grignard reagents show an enhanced reactivity.[54][55][56][57][58] The aim of this research therefore was to gain an understanding of the mutual effects of various transition metals, different spectator ligands, lithium halide additives and the substitution pattern of the respective bromobenzene derivative on the efficiency of the cross-coupling reaction.Moreover, we were highly interested to find a synthetic protocol that allows for the use of iron catalysts with yields that should be comparable to the very well working palladium catalysts.

Results and Discussion
Scheme 1 shows the coupling reactions that have been performed during the investigation described herein.0][61] All fluorinated bromobenzene derivatives 2a-m have been obtained from commercial sources.The resulting coupling products 4a-m have been purified by column chromatography.Table 1 summarizes the isolated yields of 4a-m for each of the catalytic reactions.4a-c as well as 4d and 4i have been synthesized by catalytic cross coupling reactions before.  Nevtheless, in those cases always the coupling of an aryl Grignard reagent with an alkyl halide has been investigated.From Table 1 some general trends get obvious.In all combinations that have been investigated precatalysts with dppm ligands give lower yields than those with dppe ligands with the best yields being achieved using dppp ligands.3][64] In addition, it can be concluded that Ni and Fe in most cases give very similar results whereas Pd is the most effective transition metal for the precatalysts.With regard to the used nucleophiles simple Grignard reagents show the lowest reactivity whereas the LiCl and LiBr adducts give rise to higher yields of 4a-m if all other parameters are identical.In most cases the LiBr adduct works best although there are some examples where LiCl and LiBr give very similar or identical results.It can also be seen from the results that the use of the LiCl or LiBr adducts leads to significantly increased yields for nickel and iron containing precatalysts, which are then getting acceptable to excellent.The effect of lithium halides has been rationalized by the fact that by these additives the formation of polymeric aggregates of the Grignard compounds is hampered.][67]  There also is a profound effect of the electrophile used in terms of the substitution positions being highly influential on the yield of coupling products 4a-m.All bromobenzene derivatives with fluorine substituents in ortho positions show lower yields than the corresponding electrophiles that are only substituted in meta or para position with respect to the bromine function.If ortho fluorinated bromobenzenes are used, the amount of the homo-coupling product dicyclohexyl, which is observed in GC-MS measurements of the crude reaction mixtures, increases.In addition, nucleophiles 2d, 2f and 2j with fluorine atoms in 2,3 and 2,5 position show side reactions in which obviously also C-F bonds were activated if Grignard compounds without lithium halide additives are used.The corresponding fluorine NMR spectra of crude reaction mixtures are depicted in Figure 1.If 2d is employed in the reaction the main product is the expected cross coupled compound 4d.Nevertheless, fluorine NMR also shows the formation of 4a and 4b in significant amounts besides traces of other compounds that also give rise to singlets in the 19 F NMR spectrum which means that also only one fluorine atom is present Figure 1, upper spectrum).The formation of 4a and 4b means that formally one fluorine substituent in 2d is replaced by a hydrogen atom.This might happen by a C-F bond cleavage in terms of an oxidative addition and subsequent hydrolysis of the organometallic species without an intermediate C-C coupling with the Grignard compound.The reaction mixture from the reaction of 2f also demonstrates the formation of the cross-coupling product 4f as well as the formation of 4a and 4b (Figure 1, middle spectrum).Moreover, there is another singlet of high intensity at  -118.5 ppm which might be attributed to a cross-coupling compound in which C-C bond formation also occurred at the position of the former fluorine substituent producing either 1,2-dicyclohexyl-5-fluorobenzene or 1,3-dicyclohexyl-6-fluorbenzene.The situation gets even more complicated if the trifluorinated substrate 2j is reacted with CyMgBr in the presence of a suitable catalyst.The 19 F NMR spectrum of a crude reaction mixture is depicted in Figure 1 as the lower spectrum.Besides one doublet of doublets and two additional doublets representing the expected product 4j it gets obvious that significant amounts of 4f have also been formed whereas only very small traces of 4d are visible (not marked in Figure 1).In addition, also the formation of 4a and 4b as well as of the unknown compound from the reaction of 2f is detectable.But there are at least two more compounds exhibiting two fluorine substituents as shown by doublets at  -132.5, -116.1 and -115.2 ppm and three products with only one fluorine left as verified by singlets at  -131.1, -124.6 and -111.4 ppm.In summary, there seems to be a mutual activating effect triggering an additional C-F activation reaction if two fluorine substituents are either in ortho or para position (or both) relative to each other and one of the fluorine atoms is ortho with respect to the bromine substituent.Nevertheless, these side reactions are almost completely supressed by the addition of lithium halides (Table 1).The activation of C-F bonds in Suzuki-Miyaura reactions using nickel precatalysts has recently been described. 68Nevertheless, metal fluorides as ZrF4 or TiF4 had to be added to achieve the reaction in the case of the presence of additional electron-withdrawing substituents.In addition, the formation of side products has also been shown in a highly related study on the cross coupling of CyMgBr with bromobenzene catalyzed by palladium NHC complexes. 69

Conclusions
Thirteen bromobenzene derivatives with one, two or three additional fluorine substituents have been reacted with cyclohexyl magnesium bromide or the corresponding lithium chloride or lithium bromide adducts to produce the respective cross coupling products.In the survey precatalysts of the general formula [MCl2(dppx)] (x = (CH2)n, n = 1, 2, 3) have been used with Fe, Ni and Pd as the transition metals.For all substitution positions of fluorine the dppp complexes produce the highest yield of coupling products for each of the transition metals.In addition, palladium based catalysts in almost all reactions give the highest yields of the coupling products.If not the pure Grignard reagents themselves but their lithium halide adducts are introduced to the reactions nickel and iron catalysts achieve comparable efficiencies.In terms of a cost-benefit analysis the preferred protocol therefore should be the use of the use of the lithium bromide adduct of the Grignard reagent together with [FeCl2(dppp)] as the precatalyst.The effect of fluorine substituents in ortho positions with respect to bromine is also addressed.In these cases the additional acitivation of C-F bonds is observed by 19 F NMR spectra of the crude reaction mixtures leading to undesirable multiple aryl alkyl coupling reactions.

Experimental Section
General.Bromobenzene derivatives 2a and 2b were purchased from Sigma Aldrich, 2c-m were purchased from Fluorochem Ltd.All compounds were used without further purification but were checked for purity by 1 H, 13  ).The respective deuterated solvents are used as an internal standard for 1 H and 13 C NMR spectroscopy, fluorobenzene has been used as an external standard for 19 F NMR spectroscopic investigations.Mass spectra were recorded on a Finnigan MAT SSQ 710 instrument.High-resolution mass spectra were recorded on a Finnigan MAT 95 XL using EI techniques.Elemental analyses were performed on a Leco CHNS-932 at the laboratory of the Institute of Organic Chemistry and Macromolecular Chemistry of Friedrich-Schiller-University Jena.Due to the high volatility of the products deviations from calculated values even for NMR pure compounds in some cases are higher than expected.

Table 1 .
Yields of 4a-m depending on the used nucleophiles, electrophiles and precatalysts 3a-h.The highest yield for each transition metal is presented with an italic number, the highest yield for each product is shown as a bold number