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Iron/Zinc-Cocatalyzed Directed Arylation and Alkenylation of C(sp3)–H Bonds with Organoborates Laurean Ilies, Yuki Itabashi, Rui Shang, and Eiichi Nakamura ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b02927 • Publication Date (Web): 22 Nov 2016 Downloaded from http://pubs.acs.org on November 22, 2016
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ACS Catalysis
Iron/Zinc-Cocatalyzed Directed Arylation and Alkenylation of C(sp3)–H Bonds with Organoborates Laurean Ilies*, Yuki Itabashi, Rui Shang, and Eiichi Nakamura* Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 ABSTRACT: An iron(III) salt, (Z)-1,2-bis(diphenylphosphino)ethene or its electron-rich congener, (Z)-1,2-bis[bis(4methoxyphenyl)phosphine]ethene, and a zinc(II) salt catalyze the arylation, heteroarylation, and alkenylation of propionamides possessing an 8-quinolylamide group with organoborate reagents in the presence of 1,2-dichlorobutane as oxidant at 70 °C. Stoichiometric experiments provided evidence for the involvement of an organoiron(III) species as a key intermediate for C–H activation and C–C bond formation.
KEYWORDS: iron catalysis, zinc catalysis, C(sp3)–H activation, boron compound, alkenylation, amide Among the rapidly expanding repertoire of metal-catalyzed C–H activation reactions,1 in particular C(sp2)–H activation,2 examples of C(sp3)–H activation are still scarce and their scope is rather narrow.3 For example, a standard combination of palladium and organoboron reagents4 is very effective for introducing an aryl group,5 but is applicable to the introduction of only a limited variety of alkenyl groups.6 An iron-catalyzed C(sp3)–H activation protocol that we developed recently by the use of organozinc7 or -aluminum reagents8 is not applicable for the alkenylation reaction. We report here that a combination of an organoboron reagent, an iron catalyst,9 a diphosphine ligand, and a zinc cocatalyst effects arylation, heteroarylation, and alkenylation at the β-C–H bond in α,αdisubstituted propionamides. A new ligand, electron-rich (Z)1,2-bis[bis(4-methoxyphenyl)phosphine]ethene (MeO-dppen) improved the catalytic efficiency of the alkenylation reaction. We have previously reported that an organozinc reagent functions as an aryl donor in the iron-catalyzed C–H activation of propionamides,7 but the reaction was restricted to arylation, accompanied by formation of biaryl homocoupling products.10 We hypothesized that this problem arises from the use of a highly reactive diarylzinc reagent, which delivers two organic groups to iron (cf. D, X = Ph in Figure 1), causing reductive elimination to a low-valent iron species11 (such as E in Figure 1) and biaryl. We envisioned that a milder organoborate reagent may deliver only one organic group to a high-valent iron center in each step of a catalytic cycle, which will suppress the diaryl formation and hence formation of catalytically inactive reduced iron species. The role of organoborates for this purpose was hinted by their successful use for C(sp2)–H activation, recently reported by us.12 After considerable experimentation, we found that a propionamide bearing a bidentate 8-quinolylamide directing group (Q)13 (1) reacts at 70 °C with a borate reagent prepared in situ from Ph-Bpin (pin = pinacolato) and BuLi14 in the presence of a catalytic amount of Fe(acac)3/bidentate diphosphine ligand ((Z)-1,2-bis(diphenylphosphino)ethene: dppen), a catalytic amount of Zn(OAc)2, and 1,2-dichloroisobutane (DCIB) as a
mild oxidant, to produce the corresponding β-phenylated amide (2) in 90% yield after isolation by column chromatography (eq. 1). A trace amount (5%) of starting material was recovered. Homocoupling of the organometallic reagent, which accounted for a major material loss when an organozinc reagent was used,7 was observed in 2%, suggesting that iron(III) species is not reduced by the borate reagent (see below). Notably, under similar reaction conditions, an alkenylboron reagent also reacted well with 1 to give β-alkenylated 3 in 80% yield (eq. 2), while this reaction required 20 mol % of catalyst and a more electron-rich cis-ethylenediphosphine (MeOdppen) designed for this study, to achieve 80% yield (with dppen, 50% yield).
The key reaction parameters are described in Table 1 and Supporting Information. As seen from the overall reactivity profile, Zn(II) (>0.2 equiv) was found to be essential, probably because it facilitates deprotonation of the amide’s nitrogen and transfer of the phenyl group from borate to iron.12,15,16 The use of BuMgBr instead of BuLi/Zn(II) shut off the reaction (entry 1). We note that the aryl or alkenyl group was transferred exclusively to the substrate, while the butyl group was not. Other
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borates such as phenyltrifluoroborate (entry 2) or phenylcyclic-triolborate (entry 3) were ineffective. Zinc chloride/TMEDA complex and zinc acetate gave similar results (entries 5 and 6), and we chose the latter in the present study. A catalytic amount of zinc salt sufficed to promote the reaction (entries 6 and 7). The overall data showed that dppen (entries 7–11) and the more electron-rich MeO-dppen (eq. 2 and entry 8) are suitable ligands for this reaction. A diphosphine bearing a benzene backbone (dppbz = 1,2bis(diphenylphosphino)benzene, entry 9) and a bipyridine derivative (dtbpy = 4,4′-di-tert-butyl-2,2′-bipyridyl, entry 12) also functioned as a ligand, but with lower efficiency. A monodentate phosphine (entry 10) was entirely inefficient and the reaction did not proceed at all in the absence of a ligand. Notably, a diphosphine bearing a saturated backbone, dppe (1,2-bis(diphenylphosphino)ethane) was entirely inefficient (entry 11), suggesting stabilization of a low-valent organoiron species through spin delocalization over the ligand,17 as previously reported.12 The reaction using a catalytic amount (20 mol %) of Fe(acac)2 or FeCl2 did not proceed at all. Four equiv of boron reagent was necessary, and the reaction using three equiv gave the product in 1%. One equiv deprotonates the amide’s nitrogen, one equiv acts as a base to assist C–H cleavage, and one equiv is used for arylation. 1,2-Dichlorobutane was optimal as the oxidant, as previously observed.18 We found a marked effect of the concentration on the product yield (Table 2), which was not the case in our previous study of C–H activation of aromatic amides with the same borate reagent.12 Dilution decreased the yield, and the optimal concentration was 0.80 mol/L of 1 in THF; further increasing the concentration resulted in precipitation.
Table 1. The Effect of Reaction Parameters on Phenylation of Amide 1 with 20 mol % of Catalysta
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using tridecane as an internal standard. cThis borate (6 equiv) was used instead of Ph-Bpin/base.
Table 2. The Effect of Solvent Amount on Phenylation of Amide 1 with 10 mol % of Catalysta
a
Reaction conditions: 1 (0.20 mmol), Ph-Bpin (6 equiv), BuLi (6 equiv), Fe(acac)3/dppen (10 mol %), DCIB (2 equiv) in THF at the specified concentration, 70 °C, 21 h. bThe yield was estimated by GC using tridecane as an internal standard.
As shown in Table 3, α,α-disubstituted pivalamides reacted with aryl, heteroaryl, and alkenyl boronates. Both electron-rich (entries 1–3) and electron-deficient (entries 4–6) aryl groups were efficiently introduced, and dimethylamine (entry 3) and halide groups including bromide (entries 5–7) were well tolerated. 1-Methylcyclohexylamide (entry 12) and a 2phenylamide (entry 13) that was unreactive in the reaction with organozinc reagents7 were also β-arylated with the phenyl boronate. The advantage of organoborate reagents is highlighted by the successful introduction of heteroaryl and alkenyl groups, which was not possible with organozinc reagents. For example, a thienyl group (entry 8) was introduced in high yield. Other heteroarylboronates such as 3-furanyl and or 4-pyridyl reacted sluggishly. Simple alkenyl reagents, a difficult substrate for the functionalization of C(sp3)–H bonds,6 reacted stereospecifically, as illustrated by the introduction of (E)-propenyl (entry 9) and (E)-2-cyclohexylethenyl groups (entry 11) with high (E) selectivity, and the reaction of a stereolabile (Z)-propenylboronate (E:Z ratio = 7:93) with 83% retention of stereochemistry (E:Z ratio of the product = 23:77, entry 10).
a Reaction conditions: 1 (0.2 mmol), Ph-Bpin (4.1 equiv), base (4 equiv), Fe(acac)3/ligand (20 mol %), DCIB (2 equiv) in THF (ca. 0.2 mol/L), 70 °C, 24 h. bThe yield was estimated by GC
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Table 3. Iron-Catalyzed Reaction of Pivalamides with Various Organoboronates using Dppen and MeO-dppena
corresponding zinc amide, together with BuBpin and benzene (cf. Figure 1a). Accordingly, the catalytic reaction of a preformed zinc carboxamide also proceeded (SI). A zinc salt also assists boron/iron transmetalation.12,15,16 All this evidence points to the involvement of a high-valent organoiron species such as Fe(III) as the active species that cleaves the C–H bond.8,12
A possible mechanism of the reaction stoichiometric both to iron(III) and zinc(II) cations is proposed in Figure 1, based on the above experiments, and a related study on the reaction stoichiometry.12 Zinc-assisted deprotonation gives zinc amide C (Figure 1a), and then boron/iron transmetalation gives organoiron(III) intermediate D. The lack of biphenyl suggests that D is a monophenyliron complex (X = OAc or acac); by contrast, when a more nucleophilic base such as Ph2Zn is used,7 a diphenyliron complex (D, X = Ph) forms, and its reductive elimination gives the low-valent organoiron E and biphenyl. Conversion of D to the product K via an oxidative addition mechanism (via F and an iron(V) species G) is improbable. Alternatively, C–H activation of complex D through σ-bond metathesis19,20 via H to metallacycle I is more probable. Ferracycle I accepts another phenyl group from phenylboronate and then undergoes reductive elimination to create the C–C bond and generate organoiron(I) intermediate J. This apparently unstable iron(I) species may be stabilized by electron delocalization over the ligand backbone.12,17,8
a Reaction conditions: amide (0.40 mmol), Ph-Bpin (4.1 equiv), base (4.0 equiv), Fe(acac)3/ligand (10 mol % dppen for arylation, 20 mol % MeO-dppen for alkenylation), DCIB (2 equiv) in THF (0.5 mL), 70 °C. bYield of the isolated product.
Stoichiometric reactions of amide 1 with phenyl borate (4 equiv) using 1 equiv each of Fe(acac)3 and dppen in the absence of any oxidant (eq. 3) revealed several mechanistic insights. One equiv of borate is required for deprotonation of the amide’s nitrogen, 1 equiv acts as a base for C–H cleavage, and 1 equiv is necessary for C–C bond formation. The reaction requires both 1 equiv of both Fe(acac)3 and Zn(OAc)2. The stoichiometric reaction in the absence of oxidant gave the C–H phenylation product in 47% yield and BuBpin, indicating that the DCIB oxidant used in the catalytic reaction is not essential for the C–H activation and the C–C-forming process, and that it is mainly required to reoxidize the iron species. Only a small amount (10%) of biphenyl formed, suggesting that phenyl boronate does not reduce iron. Interestingly, the use of a catalytic amount of Zn(II) did not promote the reaction at all. This may suggest the involvement of zinc as a cocatalyst for the C– H activation step. We consider that the zinc salt plays a dual role: as we previously observed through 11B NMR studies,12 deprotonation of the amide’s nitrogen by the borate alone is slow, but it is greatly accelerated by a zinc salt to give the
Figure 1. A possible reaction mechanism. The coordination stereochemistry was chosen arbitrarily. In conclusion, we have developed an iron-catalyzed reaction of α,α-disubstituted propionamides bearing a bidentate directing group with aryl, heteroaryl, and alkenyl boron reagents. The success of this reaction relies on the use of a bidentate
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directing group and a diphosphine ligand bearing a conjugated backbone, together with a mild organoboron reagent to prevent reduction of the organoiron species and to maintain the high-valent state of the organoiron(III) active species. The catalyst turnover was improved by increasing the electron density on the phosphine ligand and by increasing the concentration of the substrate. Through the stoichiometric experiments, we provided additional evidence for the involvement of an organoiron(III) species (perhaps complexed with a zinc(II) center) as a key intermediate for C–H activation and C–C bond formation.
ASSOCIATED CONTENT Supporting Information Experimental procedures and physical properties of the compounds. The Supporting Information is available free of charge on the ACS Publications website.
AUTHOR INFORMATION Corresponding Author *
[email protected];
[email protected] Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.
Funding Sources MEXT KAKENHI Grant Number 15H05754 MEXT KAKENHI Grant Number 26708011 JSPS Research Fellowship for Young Scientists No. 26-04342
ACKNOWLEDGMENTS We thank MEXT for financial support (KAKENHI No. 15H05754 to E.N. and No. 26708011 to L.I.). R.S. thanks the Japan Society for the Promotion of Science for a Research Fellowship for Young Scientists (26-04342). This work was partially supported by CREST, JST.
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