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Towards Iron-Catalysed Suzuki Biaryl Cross-Coupling: Unusual Reactivity of 2-Halobenzyl Halides
Abstract
The reaction of 2-halobenzyl halides with the borate anion Li[(Ph)(t-Bu)Bpin] leads not only to the expected arylation at the benzyl position, but also to some Suzuki biaryl cross-coupling. Preliminary mechanistic investigations hint towards the intermediacy of benzyl iron intermediates that can either: (a) directly cross-couple with the aryl boron reagent to give observed monoarylated species, or (b) undergo oxidative addition of the aryl halide to generate the diarylated species on reaction with the boron-based nucleophile.
... However, the iron-catalysed Suzuki biaryl crosscoupling reaction (Fig. 1a, M = Fe) remains problematic 27 , and early reports proved unreproducible 28,29 , which led to subsequent retractions. Indeed, to the best of our knowledge, the only example of a Suzuki biaryl cross-coupling reaction that occurs under mild conditions 30 is obtained in the coupling of 2-halobenzyl halides with the activated boronic ester 1a, which gives the expected benzyl-arylated product 2 along with some of the biaryl-coupled side product 3 31 . We speculated that the biaryl bond formation in this case may be due to the substrate 'directing' the activation of the aryl-X bond at the iron centre, as has been observed previously in the olefin-assisted alkylation of aryl chlorides 32 . ...
... We speculated that the biaryl bond formation in this case may be due to the substrate 'directing' the activation of the aryl-X bond at the iron centre, as has been observed previously in the olefin-assisted alkylation of aryl chlorides 32 . However, aryl halides with classic ortho-directing groups based on tertiary amine, ether, ester, carbamate or imine functions all failed to give the desired cross-coupling 31 . ...
Although the replacement of ubiquitous palladium catalysts with more sustainable iron-based analogues continues apace, the simple biaryl Suzuki cross-coupling reaction remains stubbornly elusive. It appears that the main issue hampering the reaction is activation of the aryl halide C-X bond. Here we show that a simple N-pyrrole amide and related directing groups on the aryl halide substrates facilitate this process by transient π-coordination to the iron centre. This allows iron-catalysed Suzuki biaryl cross-coupling to proceed, under mild conditions, with alkyllithium-activated aryl pinacol boronic esters. © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
... While the iron-catalysed Suzuki coupling of alkyl-based electrophiles has been reasonably widely investigated [24][25][26][27][28][29][30][31][32] , the equivalent biaryl cross-coupling remains elusive, although a reaction performed at 15,000 bar has been described 33 . Indeed, aside from claims that we have subsequently shown to be unfounded 21,34 , currently reported iron-catalysed Suzuki biaryl cross-couplings under synthetically reasonable conditions require either an activated heteroaryl substrate 24 or the use of substrate-directed C-X activation 35,36 . ...
The very widely exploited Suzuki biaryl coupling reaction typically requires catalysts based on palladium, but there is an increasing desire to replace this metal with a more sustainable, less expensive alternative, with catalysts based on iron being a particularly attractive target. Here we show that a simple iron-based catalyst with an N-heterocyclic carbene ligand can be used to excellent effect in the Suzuki biaryl coupling of aryl chloride substrates with aryl boronic esters activated by an organolithium reagent. Mechanistic studies suggest the possible involvement of Fe(I) as the lowest oxidation state on the catalytic manifold and show that the challenging step is not activation of the aryl chloride substrate, but rather the transmetallation step. These findings are likely to lead to a renaissance of iron-catalysed carbon–carbon bond-forming transformations with soft nucleophilic coupling partners.
... Next, for the 2-halobenzyl halides, an unusual reactivity was observed. [22] While reacting with Li[(Ph)( t Bu)B(pin)], both the mono-arylated and the diarylated products have been isolated (Scheme 5a). A detailed mechanistic investigation suggests that the low-valent iron center reacts with the benzyl halide residue and furnishes the benzyl iron intermediate, which undergoes further oxidative addition with C(sp 2 )À X with a mononuclear (S1) or binuclear (S2) pathway. ...
Transition metal‐catalyzed cross‐couplings have had a profound impact on chemical synthesis. Among the various transition metals, iron has drawn huge attention due to its cost effectiveness, range of stable oxidation states, Lewis acidic property and releatively less toxicity. Iron complexes have exhibited an efficient catalytic activity towards the cross‐coupling reaction using organomagnesium, organolithium and organozinc reagent. Organoboron compounds are also engaged as a coupling partner for Fe catalysed C−C bond forming reactions. Over the last two decades’ various iron catalysed C−C bond forming reactions have been developed. This review will summarize the chronological development in this research area along with challenges appearing especially in the past decade.
... Therefore, there is a growing incentive to replace it with more suitable options based on the earth's abundant metals [5]. In this regard, first-row transition metals are particularly attractive, including Suzuki cross-coupling reactions in the presence of nickel and iron catalysts [6][7][8][9][10][11][12][13][14]. Very recently, a few studies on the use of cobalt catalysts in this coupling reaction have been reported such as coupling of aryl triflates with aryl boron pinacol esters using a cobalt PNP-pincerbased catalyst [15]. ...
Several highly efficient and magnetically recyclable cobalt catalytic systems were prepared using magnetic chitosan and some safe and available organic compounds (Co-ligand@MNPs/Ch). The structure of these nanocomposites was confirmed by various physicochemical techniques such as FT-IR, XRD, TGA, VSM, TEM, SEM, CHNS and ICP-OES. These nano composites exhibit remarkable catalytic efficiency for Suzuki and Heck cross-coupling reactions in mild and green reaction conditions. The facile accessibility of starting materials, possible performance in air and eco-friendly conditions are merits of our catalysts. In addition, to describe and go insight to role and effect of ligands present in these catalysts, electrostatic interactions, density functional theory (DFT) model in molecular method were employed.
Graphic Abstract
... This reaction is typically catalyzed by homogeneous complexes of palladium, but due to the expense, scarcity and toxicity of palladium [3,4], there are increasing efforts to replace it with more sustainable metals, with first row transition metals attracting particular attention. Both cobaltand iron-catalyzed Suzuki biaryl cross-coupling is showing considerable promise in the formation of biaryls [5][6][7][8][9][10][11], but in these cases, the arylboron esters (or tetraorganoboronates) must be employed as the nucleophilic substrates rather than free aryl boronic acids. Early claims that aryl boronic acids could be used in iron-catalyzed Suzuki biaryl cross-coupling were subsequently retracted when the authors were unable to reproduce their results [12,13] (for a discussion, see Ref. [14]). ...
We examined the synthetic and catalytic claims that immobilization of an Fe-PNP pincer complex (1) on an amine-modified graphene oxide support yields a useful heterogeneous catalyst for the Suzuki biaryl cross-coupling reaction. Complex 1 is not formed under the reported conditions, rather the iron sulfate heptahydrate starting material (melanterite) undergoes partial dehydration to give iron sulfate tetrahydrate (rozenite). Neither rozenite nor melanterite are catalytically competent.
Graphic Abstract
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This review focuses on cross-coupling methodologies that utilize aryl and vinyl electrophiles relying on iron-based catalysts. We have outlined the most relevant and better-established methodologies; leading to the discussion of significant cases based on hard nucleophiles, with the number of examples dropping with their increasing softness. In addition, we describe several useful transformations based on reactive unsaturated nucleophiles, such as acetylenes and alkenes.
Novel 2-substituted 1,3-bis[bis(3′,5′-di-tert-butylphenyl)phosphino]propanes (SciPROP-R; 1-R), as well as their iron complexes FeCl2(SciPROP-R) 2-R, are synthesized. Single-crystal X-ray analysis and solution-phase Fe K- and L-edge XAS of 2-R reveals that these complexes maintain tetrahedral geometry and hence paramagnetic high-spin properties both in the solid state and in the solution phase. 31P NMR results demonstrate that the superior coordination ability of SciPROP-TB (1-TB) is due to the bulky tert-butyl group at position 2 of the propane-1,3-diyl linker of the ligand. These novel iron-complexes catalyze Suzuki–Miyaura-type cross coupling under mild conditions. Notably, iron(II) chloride–1-TB complex (2-TB) exhibits excellent catalytic activity owing to the high coordination ability and electron-donating nature of 1-TB, being effective for chemoselective cross coupling between various alkyl chlorides and arylboron compounds.
Over the past several decades, significant progress has been made in the field of transition-metal-catalyzed carbon–carbon bond formation. Among these advancements, iron-catalyzed reactions have garnered significant attention in organic chemistry due to their economic and environmental advantages. Iron complexes have emerged as highly promising catalysts for carbon–carbon coupling reactions. They possess several advantageous features, such as low cost, widespread availability, and lower toxicity compared to other transition metals commonly used as catalysts. Through the utilization of iron catalysts, the coupling of organometallic reagents with diverse substrates has been achieved, leading to the synthesis of a wide range of important organic compounds. In this review, the main focus is on iron-catalyzed cross-coupling reactions involving alkyl electrophiles and various organometallic reagents. These organometallic reagents include those based on organomagnesium, organozinc, organoaluminum, and organoboron nucleophiles. The objective is to create C—C bonds through these reactions. Iron salts, when combined with suitable additives or ligands, have been employed as efficient catalysts in these processes.
The mechanism of phenoxyimine (FI)-cobalt-catalyzed C(sp2)-C(sp3) Suzuki-Miyaura cross-coupling was studied using a combination of kinetic measurements and catalytic and stoichiometric experiments. A series of dimeric (FI)cobalt(II) bromide complexes, [(4-CF3PhFI)CoBr]2, [(4-OMePhFI)CoBr]2, and [(2,6-diiPrPhFI)CoBr]2, were isolated and characterized by 1H and 19F NMR spectroscopies, solution and solid-state magnetic susceptibility, electron paramagnetic resonance (EPR) spectroscopy, X-ray crystallography, and diffusion-ordered NMR spectroscopy (DOSY). One complex, [(4-CF3PhFI)CoBr]2, was explored as a single-component precatalyst for C(sp2)-C(sp3) Suzuki-Miyaura cross-coupling. Addition of potassium methoxide to [(4-CF3PhFI)CoBr]2 generated the corresponding (FI)cobalt(II) methoxide complex as determined by 1H and 19F NMR and EPR spectroscopies. These spectroscopic signatures were used to identify this compound as the resting state during catalytic C(sp2)-C(sp3) coupling. Variable time normalization analysis (VTNA) of in situ catalytic 19F NMR spectroscopic data was used to establish an experimental rate law that was first-order in a (FI)cobalt(II) precatalyst, zeroth-order in the alkyl halide, and first-order in an activated potassium methoxide-aryl boronate complex. These findings are consistent with turnover-limiting transmetalation that occurs prior to activation of the alkyl bromide electrophile. The involvement of boronate intermediates in transmetalation was corroborated by Hammett studies of electronically differentiated aryl boronic esters. Together, a cobalt(II)/cobalt(III) catalytic cycle was proposed that proceeds through a "boronate"-type mechanism.
The advancement of transition-metal-catalyzed coupling reactions has been demonstrated as a highly effective strategy for the formation of carbon-carbon bonds, which serve as the fundamental basis for organic synthetic chemistry. Given that iron represents one of the most economical and ecologically sustainable metallic elements available, the exploration and enhancement of iron-catalysed coupling reactions have garnered increasing interest within the scientific community. In recent years, numerous iron-catalysed reactions have been reported, showcasing their efficacy in establishing C-C bonds. In this minireview, we present a systematic analysis of C(sp2)-C(sp2) bond formation via iron-catalysed coupling reactions as documented in the extant literature.
Palladium-mediated cross-couplings are established as a core synthetic technology within the pharmaceutical industry for the assembly of biologically active molecules. Despite both their effectiveness and prevalence, the use of precious metals presents challenges from an environmental perspective. The ability of base metals such as Ni, Fe, and Cu to mediate carbon-carbon bond formations predates the discovery of the Pd-catalyzed methodologies though are far less established in terms of their broad scope and utility. The current chapter focuses on emerging developments in the use of non-precious metals in catalysis with potential applications in both research and development.
Two one-pot procedures for the construction of carbon-bridged diaryliodonium triflates and tetrafluoroborates are described. Strong Brønsted acids enable the effective Friedel-Crafts alkylation with diversely substituted o-iodobenzylalcohol derivatives, providing diphenylmethane scaffolds which are subsequently oxidized and cyclized to the corresponding dibenzo[b,e]iodininium salts. Based on NMR-investigations and DFT-calculations we could verify a so far undescribed existence of two stable isomers in cyclic iodonium salts substituted with aliphatic side chains in the carbon bridge.
A nickel-catalyzed C(sp3)-C(sp2) Suzuki cross-coupling of arylboronic acids and (hetero)naphthyl alcohols has been developed. A Ni(dppp)Cl2 complex showed the highest efficiency and broadest substrate scope. High functional group tolerance has been achieved where 35 compounds could be generated in good to excellent yields, including both primary and secondary benzylic alcohols. Mechanistic studies using multiple NMR techniques as well as ESI-HRMS showed that the C-O cleavage is facilitated by an activation of the benzylic alcohol through formation of a boronic ester intermediate.
Intrigued by recent reports on the surprisingly excellent activity of a range of cobalt-, iron-, copper-, and nickel-based catalysts in the Suzuki biaryl cross-coupling of simple aryl boronic acids with aryl halides, we undertook a reexamination of the syntheses of representative examples of the reported precatalysts and their application to the catalytic reaction. A reported PNP-Fe pincer complex proved to be a mixture of starting materials; a mono-Schiff base cobalt complex in fact the bis-ligated adduct and a monomeric copper(II) PNP-pincer complex a di- or oligomeric copper(I) species. In our hands, neither these complexes nor any other of the selected precatalysts investigated showed any activity in a Suzuki cross-coupling reaction of an electronically activated aryl bromide with phenyl boronic acid. Meanwhile, switching the nucleophile to the BuLi-activated phenyl boronic pinacol ester gave some promising activity with cobalt precatalysts.
An efficient synthetic protocol involving iron-catalyzed cross-coupling reactions between organolithium compounds and alkenyl iodides as key coupling partners was achieved. More than 30 examples were obtained with moderate to good yields and high stereospecificity. Gram-scale and synthetic applications of this procedure are recorded herein to demonstrate its feasibility and potential utilization.
The first iron-catalysed enantioselective Suzuki-Miyaura coupling reaction has been developed. In the presence of catalytic amounts of FeCl2 and (R,R)-QuinoxP*, lithium arylborates are cross-coupled with tert-butyl α-bromopropionate in an enantioconvergent manner, enabling facile access to various optically active α-arylpropionic acids including several nonsteroidal anti-inflammatory drugs (NSAIDs) of commercial importance. (R,R)-QuinoxP* is specifically able to induce chirality when compared to analogous P-chiral ligands that give racemic products, highlighting the critical importance of transmetalation in the present asymmetric cross-coupling system.
An efficient ligand-free iron-catalyzed cross-coupling reaction involving alkenyllithium and vinyl iodides was developed to form diene species in moderate to good yields. This new iron-catalyzed cross-coupling reaction provides a mild, inexpensive and environmentally friendly avenue towards synthesis of diversified diene derivatives.
Readily accessed cobalt pre-catalysts with N-heterocyclic carbene ligands catalyze the Suzuki cross-coupling of aryl chlorides and bromides with alkyllithium-activated arylboronic pinacolate esters. Preliminary mechanistic studies indicate that the cobalt is reduced to Co(0) during catalysis.
Readily accessed cobalt pre-catalysts with N-heterocyclic carbene ligands catalyze the Suzuki cross-coupling of aryl chlorides and bromides with alkyllithium-activated arylboronic pinacolate esters. Preliminary mechanistic studies indicate that the cobalt is reduced to Co(0) during catalysis.
Advances in iron-catalysed cross coupling from 2010-2015 are critically reviewed. In addition to a description of the systems that have emerged since 2010, the significant mechanistic work carried out to understand the mechanisms of these transformations will be discussed. An emphasis will be placed on mechanistic studies that utilize in situ reaction monitoring and the tools used to achieve this goal.
New aryl- and heteroarylboronate esters chelated by dipropanolamine are synthesised directly from boronic acids. The corresponding anionic borates are readily accessible by deprotonation and demonstrate an increase in hydrocarbyl nucleophilicity in comparison to other common borates. The new borates proved competent for magnesium or zinc additive-free, direct boron-to-iron hydrocarbyl transmetallations with well-defined iron(ii) (pre)catalysts. The application of the new borate reagents in representative Csp(2)-Csp(3) cross-coupling led to almost exclusive homocoupling unless coupling is performed in the presence of a zinc additive.
Cross-coupling between organometallic nucleophiles and organic elec-trophiles is currently one of the most widely investigated areas of organic homogeneous catalysis with iron. This overview charts the development and application of iron catalysts for cross-coupling reactions, focusing predominantly on findings over the last 5 years.
The catalytic cross-coupling reactions of organic halides or related substrates with organometallic nucleophiles form the cornerstone of many carbon–carbon bond-forming processes. While palladium-based catalysts typically mediate such reactions, there are increasing concerns about the long-term sustainability of palladium in synthesis. This is due to the high cost of palladium, coupled with its low natural abundance, environmentally deleterious extraction (∼6 g of metal are produced per ton of ore), toxicity, and competition for its use from the automotive and consumer electronics sectors. Therefore, there is a growing interest in replacing palladium-based catalysts with those incorporating more earth-abundant elements.
A copper-catalyzed Suzuki-Miyaura coupling of benzyl halides with arylboronates is described. Varieties of primary benzyl halides as well as more challenging secondary benzyl halides with β hydrogens or steric hindrance could be successfully converted into the corresponding products. Thus it provides access to diarylmethanes, diarylethanes and triarylmethanes.
The 3-coordinate 12 VE iron(II) benzyl complex [(nacnac)Fe(CH2Ph)] reacts with B(C6F5)3 to yield a paramagnetic contact ion pair with an η2-(o,m)-[PhCH2B(C6F5)3] anion, which was characterised by X-ray diffraction.
Abundant, inexpensive, and nontoxic iron salts can efficiently catalyze the cross-coupling reaction of organic electrophiles with organometallic reagents. A large variety of aryl, acyl, alkenyl, allylic, benzylic, propargylic, and alkyl electrophiles can be successfully coupled with organomagnesium, -zinc, -copper, -manganese, and -boron reagents. Coupling reactions of two organometallic reagents under oxidative conditions and of two organic halides under reductive conditions are also discussed. The reaction mechanism is controversial and various mechanisms, sometimes interconnected, in which iron can adopt different oxidation states have been proposed. Electron-transfer processes may also be involved.Keywords:iron catalysis;cross-coupling reaction
Activation of B 2 pin 2 with t BuLi facilitates the Fe-catalyzed borylation of alkyl, allyl, benzyl, and aryl halides via the formation of Li[B 2 pin 2 (t Bu)] (1). The reaction of 1 with a representative iron phosphine precatalyst generates the unique iron(I) boryl complex [Fe(Bpin)(dpbz) 2 ] (2). A lkylboronic acid derivatives are of great synthetic interest and can be prepared by a variety of methods. 1 A recent and highly attractive methodology, developed originally by Marder and co-workers, 2 relies on the borylation of alkyl halides with diboron esters, in particular bis(pinacolato)-diboron (B 2 pin 2) (Scheme 1). Originally, this method required Cu catalysts, 2,3 but the scope has been expanded to include Pd-, 4 Ni-, 5 and, most recently, Zn-based catalysts. 6 The equivalent iron-catalyzed process is highly desirable due to iron's low cost and toxicity. 7 We report that both phosphine-containing and coligand-free iron-based catalysts can be employed in the reaction to excellent effect. Furthermore, we show that a unique iron(I) boryl complex can be isolated under catalytically relevant conditions. From optimization studies (Table 1) it was clear that the barrier to success lay with the transfer of the boryl group from B 2 pin 2 to the iron center. Initial attempts at coupling
A catalyst system comprising Fe2(O(t)Bu)6 and an N-heterocyclic carbene ligand enables efficient syntheses of (hetero)biaryls from the reactions of aryl Grignard reagents with a diverse spectrum of (hetero)aryl chlorides. Amongst the alkoxide and amide counterions investigated, tert-butoxide was the most effective in inhibiting the homocoupling of arylmagnesiums.
While attractive, the iron-catalyzed coupling of arylboron reagents with alkyl halides typically requires expensive or synthetically challenging diphosphine ligands. Herein, we show that primary and secondary alkyl bromides and chlorides, as well as benzyl and allyl halides, can be coupled with arylboronic esters, activated with alkyllithium reagents, by using very simple iron-based catalysts. The catalysts used were either adducts of inexpensive and widely available diphosphines or, in a large number of cases, simply [Fe(acac)3] with no added co- ligands. In the former case, preliminary mechanistic studies highlight the likely involvement of iron(I)–phosphine intermediates.
The reactions of iron chlorides with mesityl Grignard reagents and tetramethylethylenediamine (TMEDA) under catalytically relevant conditions tend to yield the homoleptic "ate" complex [Fe(mes)3 ](-) (mes=mesityl) rather than adducts of the diamine, and it is this ate complex that accounts for the catalytic activity. Both [Fe(mes)3 ](-) and the related complex [Fe(Bn)3 ](-) (Bn=benzyl) react faster with representative electrophiles than the equivalent neutral [FeR2 (TMEDA)] complexes. Fe(I) species are observed under catalytically relevant conditions with both benzyl and smaller aryl Grignard reagents. The X-ray structures of [Fe(Bn)3 ](-) and [Fe(Bn)4 ](-) were determined; [Fe(Bn)4 ](-) is the first homoleptic σ-hydrocarbyl Fe(III) complex that has been structurally characterized.
A selective and operationally simple iron‐catalyzed cross‐coupling of aryl chlorides with alkylmagnesium halides has been developed. The reaction tolerates various functional groups and exhibits high chemoselectivity even in the presence of aryl bromides. Mechanistic studies indicate the essential role of the olefin substituent for substrate activation. Competing polymerization and reduction are effectively suppressed.
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Iron (III) complexes have been found to effectively catalyze the coupling of alkenyl halides with aryl Grignard reagents to provide arylethenes in excellent yields.
We report on a new polyfluorene derivative containing a spiroanthracenefluorene unit with a remote C-10 position that provides facile substitution of alkyl groups. An ethylhexyl group was introduced into the spiroanthracenefluorene unit and the ethylhexyl-substituted spiroanthracenefluorene was polymerized via an Ni(0)-mediated polymerization. The polymer showed a high spectral stability with respect to heat treatment, UV irradiation, and high current passage. A light-emitting device based on this polymer showed an emission in a deep blue region with CIE color coordinates of x
= 0.17 and y
= 0.12.
In the presence of Fe(acac) 3, Grignard reagents react readily with alkenyl halides (X = I, Br or Cl) in a THF/NMP mixture to give the cross-coupling products in high yields with an excellent stereoselectivity (≤99.5%). The scope of the reaction is very broad since a vast array of functional groups are tolerated (esters, nitriles, aromatic or aliphatic halides and even ketones). The procedure reported herein is an interesting alternative to the classical Pd- or Ni-catalyzed reactions, especially for preparative organic chemistry.
Functionalized arylmagnesium reagents bearing an ester, cyano, nonaflate or trialkylsityloxy group undergo fast cross-coupling reactions with alkenyl iodides or bromides in the presence of catalytic amounts of Fe(acac)(3) (5 mol%) at -20 degreesC within 1 hour resulting in the formation of the desired cross-coupling products in satisfactory yields, Excellent yields can be achieved by performing the cross-coupling reaction on solid phase by generating the Grignard reagent on the resin.
The four-coordinate iron phosphine complex FeBr2(dippe) (dippe = 1,2-bis(diisopropylphosphino)ethane) can be alkylated with Grignard or dialkylmagnesium reagents to give the unusual 14-electron iron(II) alkyls FeR2(dippe) (R = CH2SiMe3, CH2CMe3, CH2CMe2Ph, CH2Ph, CH2C6H4Me). With bulky alkyl groups or with proper control of stoichiometry, the monoalkyl species Fe(C6H2Me3)Br(dippe) and Fe(CH2CMe3)Br(dippe) may be obtained. All of these four-coordinate alkyls possess magnetic moments characteristic of high-spin species (μ = 4.9 μB) and exhibit large contact shifts in their 1H NMR spectra. An X-ray crystal structure of the p-methylbenzyl complex Fe(CH2C6H4Me)2(dippe) reveals a distorted tetrahedral geometry, with C-Fe-C and P-Fe-P angles of 111.8 (2)° and 83.33 (7)°. The Fe-C distances of 2.120 (6) Å show little change from low-spin iron(II) species, while the Fe-P distances of 2.462 (2) Å are greatly lengthened. Despite the low electron count, there are no Fe-H-C interactions or Fe-C contacts to benzylic positions in the p-methylbenzyl groups, and this fact may be accounted for on electronic grounds, although steric effects may also play a part. Specifically, the lack of empty d orbitals in these high-spin alkyls inhibits "agostic" interactions, despite the low electron counts. This behavior is consistent with the observation that the iron alkyls are incapable of olefin insertion processes that would lead to Ziegler-Natta catalytic activity. X-ray cristallographic data for Fe(CH2C6H4Me)2(dippe) at 25°C: monoclinic, space group C2/C, a = 8.957 (2) Å, b = 15.620 (5) Å, c = 22.510 (8) Å, β = 98.20 (2)°, V = 3117 (2) Å3, Z = 4, R = 5.2%, and Rw = 5.8% for 1234 data and 151 variables.
Two new selective C-C bond formation procedures are described; the Cu- catalyzed alkylation of organomanganese chlorides by alkyl halides and the Fe- catalyzed alkenylation of organomanganese chlorides by alkenyl halides. These reactions have a large scope and give high yields under mild conditions (rt, 1 h). They are highly chemoselective and allow the preparation of numerous functionalized molecules. In both cases, the presence of NMP as cosolvent (THFNMP) is determinant. For preparative organic chemistry, these two reactions compare favorably to the other related procedures since they are very easy to carry out and involve no toxic or expensive product. The Fe-catalyzed reaction is the first general Fe-catalyzed alkenylation procedure of preparative interest since no excess of alkenyl halides is required and even alkenyl chlorides can be used successfulIy.
Bis(2-methoxyethyl)aminosulfur trifluoride, (CH3OCH2CH2)2NSF3 (Deoxo-Fluor reagent), is a new deoxofluorinating agent that is much more thermally stable than DAST (C2H5)2NSF3 and its congeners. It is effective for the conversion of alcohols to alkyl fluorides, aldehydes/ketones to the corresponding gem-difluorides, and carboxylic acids to the trifluoromethyl derivatives with, in some cases, superior performance compared to DAST. The enhanced stability is rationalized on the basis of conformational rigidity imposed by a coordination of the alkoxy groups with the electron-deficient sulfur atom of the trifluoride.
Grignard reagents are coupled with alkenyl halides such as 1-bromopropene and β-bromostyrene in the presence of catalytic amounts of iron(III) complexes to afford alkenes. This cross-coupling reaction can be employed as a synthetic route for alkenes, in which primary, secondary as well as tertiary alkyl groups like isopropyl, cyclohexyl, and tert-butyl Grignard reagents are utilized. The reaction is stereospecific since trans-1-bromopropene affords only trans-butene-2 with methylmagnesium bromide and iron(III) pivalate. Furthermore, the rearrangement of branched alkyl groups such as tert-butyl has not been observed with an iron catalyst. Among various iron(III) complexes examined, tris(dibenzoylmethido)iron(III) is the most effective from the standpoint of rates and deactivation. Product and spectral studies suggest that the active catalyst is a labile iron species derived by reduction of iron(III) in situ by the Grignard component. High rates of cross coupling are limited by deactivation of the catalyst due to an aging process attributed to aggregation of the active iron species. Several mechanistic schemes are considered for cross coupling including (a) oxidative addition of alkenyl halide to a low valent alkyliron species followed by reductive elimination of the cross-coupled product and (b) assistance by reduced iron in the concerted displacement of halide at the alkenyl center by the Grignard reagent.
The cross coupling of 1-bromopropene with a variety of primary, secondary, and tertiary alkylmagnesium bromides can be effected with an iron(I) catalyst derived from tris(dibenzoylmethido)iron(III). A detailed study with ethylmagnesium bromide reveals the presence of ethane, ethylene, propylene, propenylmagnesium bromide, and 2,4-hexadiene as side products formed in addition to 2-pentene. The quantities of these products are shown to be in agreement with those expected for a complete material balance and electron balance in the catalytic process. 2-Pentene is formed stereospecifically from either (Z)- or (E)-1-bromopropene, as is the 2,4-hexadiene side product. Isotopic labeling of the ethyl group shows that ethane, ethylene, and propylene are formed by disproportionation of ethylmagnesium bromide and 1-bromopropene. A mechanism which accommodates all the products as well as the stereochemical and labeling results is proposed, in which the oxidative addition of 1-bromopropene to iron(I) is rate limiting and stereospecific. The propenyliron(III) intermediate subsequently undergoes metathetical exchange with the Grignard reagent and finally reductive elimination of the cross coupled product to regenerate the iron(I) species. Side reactions are considered to proceed from organoiron(III) intermediates by multiple exchanges and reductive disproportionations.
Chemoselective Suzuki-Miyaura coupling of primary and secondary alkyl halides is realized by using an iron/Xantphos catalyst. Primary and secondary alkyl bromides undergo the reaction to give the coupling products in good yields. Application to the synthesis of long-chain fatty acid derivatives is also described.
An effective protocol for iron-catalyzed biaryl syntheses by coupling chlorostyrenes with aryl Grignard reagents requires only mild reaction conditions and tolerates various functional groups. The underlying activation of deactivated aryl chlorides proceeds through a rate-determining coordination of the catalyst to the vinyl substituent and subsequent haptotropic migration along the conjugated π system to the site of CCl bond cleavage.
A stereospecific and high-yielding cross-coupling reaction between alkenylboron reagents and alkyl halides is described. The reaction has been achieved by using well-defined iron-bisphosphine complexes such as 1b FeCl(2)(3,5-t-Bu(2)-SciOPP), which was recently developed by the authors' group. Various nonactivated alkyl bromides and chlorides possessing a base/nucleophile-sensitive functional group can participate in the cross-coupling, demonstrating its utility for stereoselective synthesis of functional molecules bearing a carbon-carbon double bond.
In the presence of novel iron(II) chloride-diphosphine complexes and magnesium bromide, lithium arylborates react with primary and secondary alkyl halides to give the corresponding coupling products in good to excellent yields. High functional group compatibility is also demonstrated in the reactions of substrates possessing reactive substituents, such as alkoxycarbonyl, cyano, and carbonyl groups.
An efficient Hiyama coupling reaction between benzylic halide and aryltrialkoxysilane using Pd nanoparticles has been developed. This procedure accommodates various functional groups to yield a diverse range of diarylmethanes which are ubiquitous units of natural products and pharmaceuticals.
Employing co-catalytic zinc reagents facilitates the iron-catalysed Suzuki cross-coupling of tetraarylborates with both benzyl and 2-heteroaryl halides.
Combinations of N-heterocyclic carbenes (NHCs) and fluoride salts of the iron-group metals (Fe, Co, and Ni) have been shown to be excellent catalysts for the cross-coupling reactions of aryl Grignard reagents (Ar(1)MgBr) with aryl and heteroaryl halides (Ar(2)X) to give unsymmetrical biaryls (Ar(1)-Ar(2)). Iron fluorides in combination with SIPr, a saturated NHC ligand, catalyze the biaryl cross-coupling between various aryl chlorides and aryl Grignard reagents in high yield and high selectivity. On the other hand, cobalt and nickel fluorides in combination with IPr, an unsaturated NHC ligand, exhibit interesting complementary reactivity in the coupling of aryl bromides or iodides; in contrast, with these substrates the iron catalysts show a lower selectivity. The formation of homocoupling byproducts is suppressed markedly to less than 5% in most cases by choosing the appropriate metal fluoride/NHC combination. The present catalyst combinations offer several synthetic advantages over existing methods: practical synthesis of a broad range of unsymmetrical biaryls without the use of palladium catalysts and phosphine ligands. On the basis of stoichiometric control experiments and theoretical studies, the origin of the unique catalytic effect of the fluoride counterion can be ascribed to the formation of a higher-valent heteroleptic metalate [Ar(1)MF(2)]MgBr as the key intermediate in our proposed catalytic cycle. First, stoichiometric control experiments revealed the stark differences in chemical reactivity between the metal fluorides and metal chlorides. Second, DFT calculations indicate that the initial reduction of di- or trivalent metal fluoride in the wake of transmetalation with PhMgCl is energetically unfavorable and that formation of a divalent heteroleptic metalate complex, [PhMF(2)]MgCl (M = Fe, Co, Ni), is dominant in the metal fluoride system. The heteroleptic ate-complex serves as a key reactive intermediate, which undergoes oxidative addition with PhCl and releases the biaryl cross-coupling product Ph-Ph with reasonable energy barriers. The present cross-coupling reaction catalyzed by iron-group metal fluorides and an NHC ligand provides a highly selective and practical method for the synthesis of unsymmetrical biaryls as well as the opportunity to gain new mechanistic insights into the metal-catalyzed cross-coupling reactions.
Simple iron salts such as FeCl(n), Fe(acac)(n) (n = 2,3) or the salen complex 4 turned out to be highly efficient, cheap, toxicologically benign, and environmentally friendly precatalysts for a host of cross-coupling reactions of alkyl or aryl Grignard reagents, zincates, or organomanganese species with aryl and heteroaryl chlorides, triflates, and even tosylates. An "inorganic Grignard reagent" of the formal composition [Fe(MgX)(2)] prepared in situ likely constitutes the propagating species responsible for the catalytic turnover, which occurs in many cases at an unprecedented rate even at or below room temperature. Because of the exceptionally mild reaction conditions, a series of functional groups such as esters, ethers, nitriles, sulfonates, sulfonamides, thioethers, acetals, alkynes, and -CF(3) groups are compatible. The method also allows for consecutive cross-coupling processes in one pot, as exemplified by the efficient preparation of compound 12, and has been applied to the first synthesis of the cytotoxic marine natural product montipyridine 8. In contrast to the clean reaction of (hetero)aryl chlorides, the corresponding bromides and iodides are prone to a reduction of their C-X bonds in the presence of the iron catalyst.
(Chemical Equation Presented) Well-matched couples: Functionalized aryl and heteroaryl copper species obtained from the corresponding magnesium derivatives undergo Fe-catalyzed cross-coupling reactions with aryl iodides that bear keto, ester, triflate, or nitrile groups (see scheme).
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The iron(III)-catalyzed cross-coupling reaction between functionalized arylcopper reagents and aromatic iodides bearing an amide function or an unprotected quinolinone leads smoothly to polyfunctionalized biphenyls in excellent yields due to an intramolecular chelating effect of the amide group.
Transition metal catalysts, particularly those derived from the group VIII−X metals, display remarkable efficiency for the formation of carbon−carbon and carbon−heteroatom bonds through the reactions of suitable nucleophiles with organic electrophilic partners. Within this subset of the periodic table, palladium and nickel complexes offer the broadest utility, while additionally providing the deepest mechanistic insight into thus-termed “cross-coupling reactions”. The mammoth effort devoted to palladium and nickel catalysts over the past 30 years has somewhat obscured reports of alternative metal complexes in this arena. As cross-coupling reactions have evolved into a critical support for modern synthetic chemistry, the search for alternative catalysts has been taken up with renewed vigor.
A series of unprecedented organoiron complexes of the formal oxidation states -2, 0, +1, +2, and +3 is presented, which are largely devoid of stabilizing ligands and, in part, also electronically unsaturated (14-, 16-, 17- and 18-electron counts). Specifically, it is shown that nucleophiles unable to undergo beta-hydride elimination, such as MeLi, PhLi, or PhMgBr, rapidly reduce Fe(3+) to Fe(2+) and then exhaustively alkylate the metal center. The resulting homoleptic organoferrate complexes [(Me 4Fe)(MeLi)][Li(OEt 2)] 2 ( 3) and [Ph 4Fe][Li(Et 2O) 2][Li(1,4-dioxane)] ( 5) could be characterized by X-ray crystal structure analysis. However, these exceptionally sensitive compounds turned out to be only moderately nucleophilic, transferring their organic ligands to activated electrophiles only, while being unable to alkylate (hetero)aryl halides unless they are very electron deficient. In striking contrast, Grignard reagents bearing alkyl residues amenable to beta-hydride elimination reduce FeX n ( n = 2, 3) to clusters of the formal composition [Fe(MgX) 2] n . The behavior of these intermetallic species can be emulated by structurally well-defined lithium ferrate complexes of the type [Fe(C 2H 4) 4][Li(tmeda)] 2 ( 8), [Fe(cod) 2][Li(dme)] 2 ( 9), [CpFe(C 2H 4) 2][Li(tmeda)] ( 7), [CpFe(cod)][Li(dme)] ( 11), or [Cp*Fe(C 2H 4) 2][Li(tmeda)] ( 14). Such electron-rich complexes, which are distinguished by short intermetallic Fe-Li bonds, were shown to react with aryl chlorides and allyl halides; the structures and reactivity patterns of the resulting organoiron compounds provide first insights into the elementary steps of low valent iron-catalyzed cross coupling reactions of aryl, alkyl, allyl, benzyl, and propargyl halides with organomagnesium reagents. However, the acquired data suggest that such C-C bond formations can occur, a priori, along different catalytic cycles shuttling between metal centers of the formal oxidation states Fe(+1)/Fe(+3), Fe(0)/Fe(+2), and Fe(-2)/Fe(0). Since these different manifolds are likely interconnected, an unambiguous decision as to which redox cycle dominates in solution remains difficult, even though iron complexes of the lowest accessible formal oxidation states promote the reactions most effectively.