Communication pubs.acs.org/Organometallics
Dinuclear Iron Complex-Catalyzed Cross-Coupling of Primary Alkyl Fluorides with Aryl Grignard Reagents Zhenbo Mo, Qiang Zhang, and Liang Deng* State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, People’s Republic of China, 200032 S Supporting Information *
ABSTRACT: Iron-catalyzed cross-coupling of nonactivated primary alkyl fluorides with aryl Grignard reagents has been achieved by using the low-coordinate dinuclear iron complex [(IPr2Me2)Fe(μ2-NDipp)2Fe(IPr2Me2)] as the catalyst. This iron-catalyzed C(sp3)−F bond arylation reaction is applicable to a variety of aryl Grignard reagents and primary alkyl fluorides. The product pattern suggests the involvement of a radical-type mechanism for its C−F bond scission step.
T
Chart 1. Dinuclear Iron Catalysts Used in This Study
he search for a new generation of homogeneous catalysts with inexpensive, nontoxic, and environmentally benign features has led to the fast development of iron catalysis in organic synthesis,1 of which iron-catalyzed cross-coupling reactions of organic electrophiles with organometallic reagents have proved very efficient for carbon−carbon bond construction.2 With continuing efforts in this area, versatile ironcatalyzed cross-couplings of organometallic reagents with reactive electrophiles, such as acyl halides, alkenyl and alkyl triflates, iodides, bromides, and secondary alkyl halides, have been successfully developed2 and applied to the synthesis of complex organic molecules.3 However, in terms of less reactive electrophiles, e.g., electron-rich aryl halides and primary alkyl chlorides, only a handful of examples are known,4 and fluorides remain rare, in sharp contrast to the plentiful Pd-, Ni-, and Cubased catalysts.5,6 Since the conventional iron salts-based catalysts are not effective for these electrophiles, new iron catalysts, which could not only mediate the activation of carbon−halogen bonds of these less reactive halides but also concomitantly or subsequently facilitate carbon−carbon bond formation, are desired to address this challenge. In this regard, we report herein our investigation on the low-coordinate dinuclear iron complex [(IPr 2 Me 2 )Fe(μ 2 -NDipp) 2 Fe(IPr2Me2)] (IPr2Me2: 2,5-diisopropyl-3,4-dimethylimidazol-1ylidene; Dipp: 2,6-diisopropylphenyl, Chart 1),7 which is capable of catalyzing the cross-coupling of primary alkyl fluorides with aryl Grignard reagents in good yields. This study represents the first example of an iron-catalyzed C−F bond functionalization reaction and, more interestingly, has revealed the involvement of a radical-type mechanism for the C(sp3)−F bond activation step as shown below. Inspired by Holland’s work on the iron-catalyzed C−F bond hydrodefluorination reactions,8 we envisioned the potential of low-coordinate iron complexes in catalyzing cross-coupling of © 2012 American Chemical Society
organic fluorides with organometallic reagents. Hence, we examined the catalytic performance of some three- and fourcoordinate iron complexes in addition to simple iron salts in the reaction of n-C8H17F with p-Me-C6H4MgBr in THF. As shown in Table 1, the iron compounds [Fe(acac) 3 ] 4a and (FeCl3)2(TMEDA)3 (TMEDA = N,N,N′,N′-tetramethylethylenediamine),9 which are well known for catalyzing the crosscoupling of reactive organic halides with aryl Grignard reagents, do not promote C−F bond arylation (entries 1 and 2), but induce defluorination of n-C8H17F. A similar situation occurred in the cases of the low-coordinate complexes [Fe(NTMS2)2]2,10 [Fe(Mes)2]2,11 and (IPr2Me2)Fe(Mes)27 (entries 3−5; TMS = trimethylsilyl; Mes = 2,4,6-trimethylphenyl). As the defluorination products (3−5) dominate in these trials, the iron complexes seem amenable to facilitating C−F bond cleavage, but incapable of promoting further carbon−carbon bond formation. The dinuclear iron complex [(IPr2Me2)Fe(μ2NDipp)2Fe(IPr2Me2)] (cat. 1)7 shows a different catalytic performance. Addition of the catalyst to the reaction mixture gave a red-brown solution. After 48 h GC-MS analyses revealed the formation of the cross-coupling product p-methyl-noctylbenzene and the defluorination products in 87% and 5% Received: July 29, 2012 Published: August 31, 2012 6518
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Table 2. Iron-Catalyzed Arylation of n-Octyl Fluoride
Table 1. Influence of the Iron Catalysts
GC yield (%)a entry
iron compound
2
3+4+5
6
1
1 2 3 4 5 6 7 8
Fe(acac)3 (FeCl3)2(TMEDA)3 [Fe(NTMS2)2]2 [Fe(Mes)2]2 (IPr2Me2)Fe(Mes)2 cat. 1b cat. 2b none
trace 0 0 7 0 87 71 NR
75 37 79 56 23 5 12
trace 40 trace trace trace 12 31
25 63 21 37 77 7 17
a GC yields are based on the fluoride. bcat. 1: [(IPr2Me2)Fe(μ2NDipp) 2 Fe(IPr 2 Me 2 )]; cat. 2: [F(IPr 2 Me 2 )Fe(μ 2 -NDipp) 2 Fe(IPr2Me2)F].
Data in parentheses are isolated yields based on the fluoride after column chromatography. bThe reaction was run at room temperature.
a
Table 3. Iron-Catalyzed C(sp3)−F Bond Phenylationa,b
yields, respectively (entry 6). The diferric complex [F(IPr2Me2)Fe(μ2-NDipp)2Fe(IPr2Me2)F] (cat. 2)7 could also catalyze the cross-coupling reaction and afforded the product in a slightly lower yield (entry 7). Noting Matsubara’s report on the C−F bond cleavage reactions of alkyl fluorides with PhMgCl without a transition metal catalyst, which gave arylation products in low yields,12 as well as Kambe’s copper-catalyzed C(sp3)−F bond phenylation reactions,13 the control experiment of treating p-Me-C6H4MgBr with n-C8H17F in the absence of iron complexes was performed (Table 1, entry 8). While atomic absorption spectroscopy analyses on this reaction mixture indicate the presence of copper in low concentration (less than 10 ppm),14 no reaction was observed for this trial since GC-MS analyses show the full retention of n-C8H17F. These results suggest the observed C(sp3)−F bond phenylation reactions in entries 5 and 6 are less likely facilitated by impurity or trace metal contamination and confirm the uniqueness of the dinuclear iron complexes in catalyzing the C(sp3)−F bond phenylation reaction. Subsequently, we examined the impact of the arene substituent of Grignard reagents on the reaction yields by the reaction of n-C8H17F with two equivalents of Grignard reagents at room temperature or at 60 °C when the rates were slow at room temperature. As shown in Table 2, this reaction did not exhibit a clear dependence on the electronic nature of the substituents, as the corresponding cross-coupling products were obtained in high yields with either electron-donating (entries 1−7) or electron-withdrawing (entries 8 and 9) groups attached to the aryl ring.15 In addition to phenyl Grignard reagents, naphthyl Grignard reagents could also be used as the nucleophiles (entries 11 and 12). Notably, besides the crosscoupling products, small amounts of n-octane and octenes were also observed in all cases.15 The scope of fluorides was examined using p-Me-C6H4MgBr as the nucleophile. The dinuclear iron complex can selectively catalyze the arylation of a variety of primary alkyl fluorides (Table 3), but is ineffective for cyclohexyl, adamantyl, and phenyl fluorides. The selectivity might come from the different steric properties of the alkyl fluorides and is distinct from Kambe’s nickel- and copper-catalyzed C−F bond functionalization reactions, which work for both primary and secondary alkyl
a
Ar = p-methylphenyl. bData in parentheses are isolated yields based on fluorides after column chromatography. cFour equivalents of Grignard reagents was used.
fluorides.6b−d,g,13 As shown in Table 3, among the examined primary fluorides, the phenylation of simple alkyl fluorides, noctyl and n-hexyl fluoride, could be accomplished in high yields (entries 1 and 2). With 6-fluoro-1-phenyl-1-hexene, the reaction gave both phenylation and defluorination products in 67% and 16% yields, respectively, but no cyclization product (entry 3). When 1,6-difluorohexane was used, both the double phenylation product, 1,6-di(p-tolyl)hexane, and monophenyla6519
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tion/defluorination product, p-methylhexylbenzene, were formed (entry 4). The reaction can also tolerate certain functional groups. As depicted in entries 5−7, the reactions using 3-(2′-furyl)propyl fluoride, 2-(2′-fluoroethyl)-1,3-dioxane, and 2-(3-fluoropropyl)-1-methylindole gave the crosscoupling products in decent yields along with certain amounts of the defluorination products. The increased yields of the byproducts in entries 3−7 again suggest this iron-catalyzed cross-coupling reaction might be sensitive to the steric bulkiness of alkyl fluorides. To understand the role of the dinuclear iron catalyst, we performed the stoichiometric reaction of [(IPr2Me2)Fe(μ2NDipp)2Fe(IPr2Me2)] with n-C8H17F or p-Me-C6H4MgBr in THF, but neither reaction took place at either room temperature or 60 °C, as indicated by their intact 1H and 19F NMR spectra. These results indicate [(IPr2Me2)Fe(μ2NDipp)2Fe(IPr2Me2)] might be the resting state of genuine catalytic species in the catalytic cycle. To shed light on the mechanism of the C(sp3)−F bond scission step, the reaction employing “radical clock” cyclopropylmethyl fluoride has been performed. As shown in Scheme 1, this reaction gave not only
Scheme 2. Proposed Reaction Mechanism
nucleophilic substitution reactions of alkyl fluorides have been well documented in the literature,20 a nucleophlic substitution mechanism, possibly via the reaction of the iron-aryl intermediate (A) with alkyl fluorides, might also be present as a parallel route during the reaction course. In conclusion, by using the low-coordinate dinuclear iron(II) complex [(IPr2Me2)Fe(μ2-NDipp)2Fe(IPr2Me2)] as the catalyst we have achieved the first example of an iron-catalyzed cross-coupling reaction with organic fluorides as the electrophiles. This iron-catalyzed C(sp3)−F bond arylation reaction is applicable to a variety of aryl Grignard reagents and primary alkyl fluorides and involves a radical-type mechanism that is distinct from the known Ni- and Cu-catalyzed C(sp3)−F bond functionalization reactions.5b Currently, we are trying to investigate the reaction mechanism in detail and expand the substrate scope upon catalyst modification.
Scheme 1. Cross-Coupling of Cyclopropylmethylene Fluoride with p-Me-C6H4MgBr
the ring-opening product 4-methyl-1-(3′-butenyl)benzene but also the cyclopropyl derivative 4-methyl-1-cyclopropylmethylbenzene, along with 4,4′-dimethylbiphenyl. While our control experiment has confirmed the inertness of cyclopropylmethyl fluoride toward p-Me-C6H4MgBr without the addition of the iron catalyst, the formation of both phenylation products resembles the one-electron oxidation reaction between (TMEDA)Fe(Mes)2 and cyclopropylmethyl bromide16 and suggests the involvement of iron-mediated radical processes. Based on these results, a radical-type mechanism was proposed for this dinuclear iron complex-catalyzed crosscoupling reactions. As shown in Scheme 2, the reaction might proceed by the displacement of one IPr2Me2 ligand in [(IPr2Me2)Fe(μ2-NDipp)2Fe(IPr2Me2)] by an aryl anion to afford a low-coordinate anionic intermediate [(IPr2Me2)Fe(NDipp)2Fe(Ar)]− (A).17 An alkyl fluoride molecule (R-F) might then interact with this low-coordinate intermediate in a single electron-transfer manner to produce an alkyl radical R• and a transient aryliron(III) fluoride (or an iron(II) species bonding with an aryl radical (Ar•)). Subsequent coupling of these two radicals would afford the cross-coupling product (ArR) and a fluoride-bound intermediate B. B might then react with ArMgBr to regenerate intermediate A. On the other hand, when the rate of radical coupling is not fast enough, the side reactions of radical decomposition may take place, generating defluorination products and biaryls.18 This mechanism is supported by the known capability of the dinuclear ironimido complex in mediating electron transfer7 and the precedent examples of radical-type C(sp3)−F bond activation reactions.19 Notably, as chelating- and Lewis acid-assisted
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ASSOCIATED CONTENT
S Supporting Information *
Detailed experimental procedures; characterization data for starting materials and cross-coupling products. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the National Basic Research Program of China (973 Program, No. 2011CB808705) and the National Natural Science Foundation of China (Nos. 20872168, 21002114, and 21121062) for financial support.
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REFERENCES
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