Air-Stable Iron-Based Precatalysts for Suzuki−Miyaura Cross-Coupling Reactions between Alkyl Halides and Aryl Boronic Esters

Abstract

The development of an air-stable iron(III)-based precatalyst for the Suzuki−Miyaura cross-coupling reaction of alkyl halides and unactivated aryl boronic esters is reported. Despite benefits to cost and toxicity, the proclivity of iron(II)-based complexes to undergo deactivation via oxidation or hydrolysis is a limiting factor for their widespread use in cross-coupling reactions compared to palladium-based or nickel-based complexes. The new octahedral iron(III) complex demonstrates long-term stability on the benchtop as assessed by a combination of ¹H NMR spectroscopy, Mössbauer spectroscopy, and its sustained catalytic activity after exposure to air. The improved stability of the iron-based catalyst facilitates an improved protocol in which Suzuki−Miyaura cross-coupling reactions of valuable substrates can be assembled without the use of a glovebox and access a diverse scope of products similar to reactions assembled in the glovebox with iron(II)-based catalysts.

INTRODUCTION

Over the past four decades, the palladium-catalyzed Suzuki−Miyaura cross-coupling reaction has become a prominent and powerful tool for the assembly of C(sp²)−C(sp²) bonds.¹ The impact of the Suzuki−Miyaura reaction is especially apparent in the pharmaceutical industry, where it is employed in nearly 25% of reported syntheses of medicinally active small-molecule drugs.² Despite this impressive utility, cross-coupling reactions catalyzed by palladium-based complexes commonly undergo β-hydride elimination side reactions that often limit the reaction to sp-hybridized or sp²-hybridized substrates,³ which in turn is likely an underlying reason for the disproportionate representation of mostly flat molecules in medicinally relevant small-molecule drugs.² To explore the efficacy of pharmaceutical targets possessing three-dimensional features, first-row transition metal catalysis has emerged as a promising alternative. Of the first-row transition metals, nickel-based complexes have been most commonly investigated for cross-coupling catalysis.^4–9 In comparison, reactions catalyzed by iron-based complexes have historically received less attention,^10–12 despite the reduced cost and toxicity of iron when compared to that of palladium and the reduced toxicity of iron when compared to nickel.¹³ One challenge facing the broad implementation of iron-based catalysts in cross-coupling reactions is the propensity for catalyst precursors to undergo rapid deactivation upon exposure to air or water due to facile oxidation and/or hydrolysis reactions that form iron oxides (Figure 1a). Bench-stable iron salts (e.g., FeCl₃, Fe(acac)₃) have been employed as catalyst precursors in cross-coupling reactions involving Grignard reagents^14–17 and alkenes,^18–21 but their efficient activity toward boron-containing coupling partners remains elusive. Moreover, examples of Suzuki−Miyaura reactions between alkyl halides and aryl boronic esters catalyzed by iron-based complexes often require the use of reactive lithium amide bases²² or substrates preactivated by highly pyrophoric alkyllithium bases.^23–25 Proposed catalytic cycles for these reactions often invoke the intermediacy of highly reactive and low-valent iron intermediates.^26–29 As a result, cross-coupling reactions catalyzed by iron-based catalysts usually demand the use of stringently air-free and water-free conditions, which limit their practical implementation on scale.

Figure 1.

(a) Suzuki–Miyaura cross-coupling of alkyl halides with aryl boronic esters catalyzed by iron-based complexes, which required long-term storage and reaction setup in an air-free glovebox;³¹ (b) this work, which describes an iron-based complex that is bench stable and active for Suzuki–Miyaura cross-coupling reactions without the requirement of an air-free glovebox.

In response to this challenge, we have been developing iron-based catalysts for Suzuki−Miyaura cross-coupling reactions that have begun to address some of these limitations.³⁰ While these reactions no longer require the preactivation of boronic esters with alkyllithium reagents, they still required iron(II) catalyst precursors that prevented assembly of the reaction on the bench. We hypothesized that iron(III) catalyst precursors would be less prone to oxidation and hydrolysis compared to iron(II) catalyst precursors we have used previously (Figure 1a). Additionally, we speculated that the highly reducing conditions of the cross-coupling reaction would generate in situ iron(II)-based intermediates that are often proposed to be catalytically relevant for successful cross-coupling. Herein, we disclose the synthesis and characterization of a new iron(III)-based precatalyst that is air-stable, stable on the benchtop for at least 9 months, and active for the cross-coupling of alkyl halides with aryl boronic esters (Figure 1b).

RESULTS AND DISCUSSION

Recently, we reported the design of iron-based complexes supported by β-diketiminate ligands that proved highly effective for catalyzing Suzuki−Miyaura cross-coupling reactions.³¹ The reaction was capable of assembling molecules with functionality common in many pharmaceuticals, such as functionalized heteroaromatic rings. It was also capable of carrying out difficult cross-coupling reactions, such as those involving tertiary alkyl halides. Utilizing these electrophiles in cross-coupling reactions results in the synthesis of all-carbon quaternary centers, a challenging motif to obtain for most synthetic methodologies. Despite their synthetic utility, the reactions required that discrete iron(II) complexes containing the β-diketiminate ligand be synthesized as opposed to reactions where ligands were added to iron-based catalyst precursors. These discrete complexes were not stable to oxygen or water and rapidly (i.e., within minutes) underwent decomposition when exposed to ambient air (Figure 1a). Therefore, to obtain an air-stable catalyst precursor, we targeted discrete iron(III) catalyst precursors containing the β-diketiminate ligand. Initially, we attempted to synthesize an iron(III) halide complex using the iron(III) salt FeCl₃ in place of FeCl₂, but ¹H NMR spectroscopy of the resulting product was identical to that of the previously used iron(II) complex 1. An effective magnetic moment measured in the solution state for the product confirmed that the iron(III) catalyst precursor was reduced in situ by the deprotonated ligand (μ_eff = 5.20 μ_B) (Scheme 1a). We next attempted to oxidize the iron(II) complex with the addition of an external oxidant, ferrocenium hexafluorophosphate (Scheme 1b). An effective magnetic moment measured in the solution state for the resultant purple crystals supported the successful oxidation to a high-spin iron(III) complex (μ_eff = 6.54 μ_B), and the structure was confirmed by X-ray crystallographic characterization as the monomeric, neutral iron(III) dichloride complex 2 that displayed a distorted tetrahedral coordination environment (Figure 2a, CCDC 2088833). Iron(III) halide complexes that contain the β-diketiminate ligand have not been previously reported. However, Holland and co-workers have previously synthesized four-coordinate β-diketiminate iron(III) amido complexes³² that feature similar Fe−N bond lengths compared to complex 2. These bond lengths are shorter than those reported for analogous four-coordinate iron(II) halide complexes,^31,32 which are consistent with an increase in oxidation state. In addition to the iron(III) halide complex 2, we also pursued the synthesis of the iron(III) complex 3. Since the iron(III) salt Fe(acac)₃ is often used as a bench-stable catalyst precursor and β-diketiminate ligands are isoelectronic and isolobal to acetylacetonate ligands, we reasoned that replacing an acetylacetonate ligand in Fe(acac)₃ with a β-diketiminate ligand could lead to an iron(III) complex containing the β-diketiminate ligand that was active for cross-coupling catalysis and was air-stable. We thought such a complex could be synthesized through ligand substitution reactions between Fe(acac)₃ and deprotonated β-diketiminate ligands. As expected, the addition of the deprotonated β-diketiminate ligand to Fe(acac)₃ resulted in the formation of a dark green compound 3 (Scheme 1c). An effective magnetic moment measured in the solution state for complex 3 was consistent with a high-spin iron(III) center (μ_eff = 7.04 μ_B). X-ray crystallographic characterization of this complex confirmed the formation of an octahedral iron complex supported by one β-diketiminate ligand and two acetylacetonate ligands (Figure 2b, CCDC 2088834). The Fe−N bond lengths of compound 3 are comparable to those found in previously reported β-diketiminate iron(II) complexes³³ but longer than those found in previously reported β-diketiminate iron(III) complexes,^32–35 though the reported β-diketiminate iron(III) examples are limited to three- and four-coordinate iron(III) amido complexes. The Fe−O bond lengths of compound 3 are likewise longer than those found in Fe(acac)₃ (average bond length = 1.991(8)Å).³⁶ The octahedral geometry of complex 3 also gives rise to a smaller N−Fe−N bond angle than that observed in other β-diketiminate iron(III) complexes, though O−Fe−O bond angles are also smaller than those observed in Fe(acac)₃ (average O−Fe−O bond angle = 87.47(3)°).³⁶ In comparison to 2, Fe−N bond distances in 3 are significantly longer and the N−Fe−N bond angle is more acute. The differences in bond metrics between 2 and 3 may be due to the different geometry of two complexes or due to the trans-influence of acac ligands in octahedral 3 that is absent in the distorted tetrahedral complex 2.

Scheme 1.

(a) Attempted Synthesis of an Iron(III) Complex Supported by a β-Diketiminate Ligand through the Addition of FeCl₃, (b) Synthesis of a Neutral Iron(III) Dichloride Complex Supported by a β-Diketiminate Ligand via the Oxidation of the Analogous Iron(II) Complex, and (c) Synthesis of an Air-Stable Iron(III) Complex Supported by a β-Diketiminate Ligand and Two Acetylacetonate (acac) Ligands

Figure 2.

X-ray crystal structures of complexes 2 and 3 with selected bond metrics. Thermal ellipsoids are drawn at the 50% probability level; cocrystallized solvent molecules and hydrogen atoms are omitted for clarity.

When iron(II) complex 1 was subjected to our previously established standard cross-coupling conditions (Figure 1b) following its exposure to air for 1 h, the Suzuki−Miyaura reaction between bromocycloheptane and phenyl boronic acid pinacol ester produced phenylcycloheptane in significantly reduced yield (12 ± 7%), compared to reactions where 1 was not exposed to air (96 ± 3%). Conversely, an initial attempt to subject complex 2 to our standard cross-coupling conditions following exposure to air for 1 h delivered the product in 60% yield (compared to 85% without air exposure), and complex 3 delivered the product in 71 ± 11% yield (compared to 83 ± 6% without air exposure) under the same conditions. We have previously proposed a catalytic cycle for the iron-catalyzed Suzuki−Miyaura cross-coupling reaction, which is our current working mechanistic hypothesis (Scheme 2).²⁹ In this proposed mechanism, iron(II) halide precatalyst I is activated by salt metathesis with the lithium amide base. Iron(II) amide species II activates the electrophile and the nucleophile via halogen abstraction to yield intermediate III and transmetalation to yield intermediate IV, respectively. The carbon-centered radical formed by halogen atom abstraction recombines with IV, followed by reductive elimination from V to deliver the cross-coupled product. Finally, catalyst turnover is achieved by comproportionation between III and VI to regenerate an equivalent of I and an equivalent of II. We hypothesized that the presence of a strong reductant, such as lithium amide, could enable iron(III) precursors 2 and 3 to enter the catalytic cycle as iron(II) amide species II (Scheme 2). Alternatively, iron(III) precursors could participate in comproportionation with the low-coordinate iron(I) species VI generated from reductive elimination to enter the catalytic cycle. Ongoing investigations into the precise mechanism of activation of iron(III) precatalysts is beyond the scope of this report and is the topic of current investigations.

Scheme 2.

Working Mechanistic Hypothesis for the Cross-Coupling Reaction of Alkyl Halides and Aryl Boronic Esters Catalyzed by β-Diketiminate Iron(II) Complexes^a

^aPossible mechanisms for activation of iron(III) analogues are highlighted in red.

With the competency of an iron(III) precatalyst for Suzuki−Miyaura cross-coupling established, we next sought to assess the benchtop stability of the iron complexes. The ¹H NMR spectrum of iron chloride complex 2 displayed no change immediately following exposure to air, which is consistent with our working hypothesis that these compounds would be less sensitive to oxidation. However, further exploration revealed that 2 was not indefinitely stable to air because a color change of the sample accompanied by loss of all paramagnetic resonances in the ¹H NMR was observed within 24 h after initial exposure to air. This finding suggested that catalyst deactivation occurred. Conversely, complex 3 remained stable in the solid state for up to 9 months following its storage in a benchtop desiccator, as determined by ¹H NMR spectroscopy. To gain further insight, the speciation of the iron center in complex 3 was also examined using ⁵⁷Fe Mössbauer spectroscopy. The 80 K ⁵⁷Fe Mössbauer spectrum of a powder of iron(III) complex 3 features a broad doublet with Mössbauer parameters of δ = 0.47 mm/s and |ΔE_Q| = 0.82 mm/s, consistent with a high-spin iron(III) species (Figure 3a). Similar broadening has been previously observed in other high-spin iron(III) complexes,^37,38 though contributions to broadening from the presence of residual Fe(acac)₃ cannot be excluded. Most importantly, the spectrum of a sample of 3 taken after 4 months of continued exposure to air displayed no substantial changes from that of a freshly synthesized sample of the same complex. A similar analysis of the iron(II) complex 1 before and after only 1 h of exposure to air (Figure 3b) displayed marked differences in the Mössbauer spectra that suggest near-complete conversion of the iron(II) complex (δ = 0.90 mm/s and |ΔE_Q| = 2.41 mm/s) to a mixture of iron complexes, the two major components of which have Mössbauer parameters consistent with iron(III) complexes formed from rapid oxidation (δ = 0.42 mm/s and |ΔE_Q| = 0.81 mm/s, 48% of total iron, blue component; δ = 0.38 mm/s and |ΔE_Q| = 1.37 mm/s, 46% of total iron, red component). This rapid oxidation is further supported from changes in the ¹H NMR spectrum of the complex as well as its physical appearance. These changes are also consistent with the decreased yield observed for reactions where 1 was exposed to air for 1 h compared to reactions carried out entirely in the glovebox (vide supra).

Figure 3.

(a) Comparison of the 80 K ⁵⁷Fe Mössbauer spectra of a powder of 3, (i) prior to and (ii) following exposure to air for 4 months. (b) Comparison of the 80 K ⁵⁷Fe Mössbauer spectra of the previously synthesized iron(II)-based cross-coupling precatalyst 1, (i) prior to and (ii) following exposure to air for 1 h. The latter spectrum features three iron species with the following parameters: red component, δ = 0.38 mm/s, |ΔE_Q| = 1.37 mm/s (46% of total iron); blue component, δ = 0.42 mm/s, |ΔE_Q| = 0.81 mm/s (48% of total iron); and green component, δ = 1.34 mm/s, |ΔE_Q| = 2.55 mm/s (6% of total iron).

These sets of experiments demonstrate that the iron(III) complex 3 is less prone to degradation in air, supporting our hypothesis that higher oxidation state iron species are less prone to decomposition on the benchtop than iron(II) catalyst precursors. In addition to the oxidation state, we speculate that the iron(II) halide complex 1 is less stable to air than iron(III) complex 3 due to the more rapid hydrolysis of iron halides compared to iron acetylacetonate complexes. This hypothesis is also consistent with the observed behavior of complex 2, which is an iron(III) halide complex that rapidly undergoes deactivation toward cross-coupling at room temperature, presumably because hydrolysis rather than oxidation occurs. Thus, with the proper choice of oxidation state and supporting ligands, air-stable and moisture-stable catalyst precursors for the Suzuki−Miyaura cross-coupling reaction can be obtained.

Having demonstrated the benchtop stability of the iron-based complex, we sought to evaluate conditions for the catalytic cross-coupling reaction in hopes of eliminating the need to use a glovebox for the reaction (Table 1). Low yields were obtained when the reaction was carried out with commercially available Fe(acac)₃ and β-diketiminate ligand in place of iron complex 3 synthesized prior to the cross-coupling reaction (Table 1, entry 1). All other reactions reported in Table 1 were carried out with iron complex 3 that was exposed to air for at least 4 weeks (see the Experimental section for detailed procedures). The yield obtained after 4 weeks of exposure to air (56 ± 1%) was lower than the yield of the reaction carried out after 1 h of exposure to air (71 ± 11%). However, increasing the equivalents of the base to 2 resulted in better yields (80 ± 6%) compared to when 1.2 equiv of the base were used (Table 1, entries 2−6). Further investigation revealed that reactions carried out with 2.0 equiv of base were best to obtain reproducible yields regardless of how long complex 3 was exposed to air: complex 3 that was not exposed to air gave a nearly identical yield (83 ± 6%) as the reaction carried out after 3 was exposed to air for 4 weeks, and a reaction carried out after complex 3 had been exposed to air for 9 months delivered the cross-coupled product in 79% yield. Reactions run with 2 equiv of base proved to be optimal to obtain high yields reproducibly because further increasing the equivalents of base led to lower isolated yields (Table 1, entries 5 and 6). Cognizant of the toxicity of benzene as an ICH class 1 solvent,³⁹ more environmentally friendly solvents like 2-methyl tetrahydrofuran and anisole (both class 3 solvents) were also evaluated for the reaction (Table 1, entries 7 and 8). While reactions carried out in 2-methyl tetrahydrofuran led to a slight drop in yield compared to reactions carried out in benzene, reactions in anisole gave almost the same yield as reactions in benzene. While benzene was used as the primary solvent for the remainder of this study due to its relative ease of removal from the reaction mixture, we anticipate that anisole can be used as a replacement for benzene industrially.

Table 1.

Optimization of Reaction Conditions^g

entry	LiNMeEt (equiv)	solvent	yield (%)
			gloveboxa	Schlenk linea
1b	1.2	benzene	24c	n/a
2	1.2	benzene	56 (±1)c	40d
3	1.5	benzene	66c	43d
4	2.0	benzene	80 (±6)c,f	66 (±4)d,f
5	2.5	benzene	45c	52d
6	3.0	benzene	22c	0d
7	2.0	2-MeTHF	69c	49d
8c	2.0	anisole	78c	22d
9c	2.0	1:6 anisole:benzene	99c	69d
10e	2.0	1:6 anisole:benzene	n/a	74 (±3)f
11	2.0	benzene	n/a	90c

^aSee the Experimental Section for details regarding the reaction assembly.

^bFe(acac)₃ combined with the β-diketiminate ligand in place of a discrete catalyst.

^cLiNMeEt added as a uniformly sieved solid.

^dLiNMeEt added as a dispersion in anisole.

^eLiNMeEt synthesized in anisole in the reaction vessel immediately prior to addition of the catalyst and substrates.

^fAverage of five trials.

^gUnless otherwise stated, the iron precatalyst was exposed to air for 4 weeks prior to the reaction.

Our previous results suggest that using a lithium amide base is helpful for iron-catalyzed cross-coupling reactions to avoid the irreversible formation of inactive iron aggregates.²² Unfortunately, using alkyl amide bases precludes a facile reaction setup on the benchtop.⁴⁰ Because lithium amide is moderately soluble in anisole and employing anisole as a solvent did not adversely affect the outcome of the reaction in the glovebox, a procedure was developed which involved dispensing a dispersion of lithium amide in anisole into the reaction vessel for application on the Schlenk line. Reaction setup using this procedure produced the desired product, although the lower yield was generally observed compared to reactions setup and carried out inside of a glovebox with the same solvent ratio (Table 1, entry 9). Higher yields could be obtained by deprotonating the amine with n-butyllithium in anisole in the reaction vessel on the Schlenk line immediately prior to the addition of the catalyst and substrates under a positive flow of inert gas (Table 1, entry 10). Employing this procedure, yields were comparable to reactions assembled in the glovebox and employing benzene as the solvent (cf. Table 1, entry 4). Using this procedure, the reaction could be performed on a gram scale, enabling isolation of the desired cross-coupled product in 82% yield.

It is important to mention that discrepant yields obtained between the reactions carried out in the glovebox and on Schlenk lines are chiefly due to the manner in which lithium amide is added to the reaction mixture, rather than the air sensitivity of the catalyst precursor or the fidelity of the air-free procedure. To illustrate this fact, the cross-coupling reaction was carried out using solid lithium amide that was sieved so that the particle size introduced to the reaction was 250 μm or smaller (Table 1, entry 11). Lithium amide prepared in this way was then weighed into a sealed reaction vessel inside a glovebox, which was evacuated on a Schlenk line prior to the addition of complex 3, reaction substrates, and the solvent (weighed out/dispensed on the bench) under a positive pressure of inert gas. The product yield was comparable to those from reactions using complex 1 inside of a glovebox (96%, vide supra), which also employed sieved lithium amide rather than an in situ suspension in anisole. We hypothesize that lithium amide benefits from being sieved because it helps regulate lithium amide dissolution, which is only partially soluble in the aromatic solvents used. Consequently, the partial solubility of the base in aromatic solvents is beneficial to carrying out the reaction in benzene and anisole rather than 2-methyl tetrahydrofuran because these solvents provide a convenient way to gradually introduce the base to the reaction as it proceeds.

While the reaction involving sieved lithium amide gave superior yields, this procedure required the use of a glovebox. Thus, using the optimal procedure that does not require a glovebox (i.e., the procedure that involves deprotonation of the amine in situ), the substrate scope of the reaction was explored next (Table 2). Heteroaromatic-containing substrates 4−10, which were amenable to our previously reported method,³¹ were also viable for cross-coupling with the air-stable catalyst. These substrates are highly represented in pharmaceutically relevant compounds and demonstrate how the new protocol may have value to medicinal and process chemists. Primary, secondary, and tertiary alkyl halides 11−16 were well-tolerated, as well as protected amine 17 and a protected alcohol 18. While the need for the lithium amide base somewhat limited the functional group tolerance of the method (e.g., esters, ketones, and free amines were not tolerated), an alkyl halide containing a nitrile resulted in some cross-coupled product 19. All reactions delivered the desired cross-coupled product regardless of whether they were assembled in the glovebox or on the Schlenk line, although lower product yield is generally observed when compared to analogous reactions using the previously reported β-diketiminate iron(II) catalyst precursors in the glovebox (see Table S1). However, to emphasize that discrepant yields are chiefly due to the manner in which lithium amide is added to the reaction mixture and not the air sensitivity of the catalyst precursor nor the inability for the iron(III) precursor to be reduced to the catalytically active species, the procedure using solid lithium amide that was sieved prior to addition of 3 and the other reagents using the Schlenk line as described in Table 1, entry 11 was tested for substrate 10 to obtain the product in 67% yield, which was similar to the 68% yield obtained when using complex 1 inside of a glovebox. Thus, we recommend that practitioners that have access to a glovebox prepare a stock suspension of lithium amide in anisole,⁴¹ which can then be dispensed on the Schlenk line as needed.

Table 2.

Substrate Scope for Cross-Coupling Reactions Performed without the Aid of a Glovebox Using Air-Stable Complex 3 as a Catalyst Precursor

CONCLUSIONS

In conclusion, an air-stable iron(III)-based catalyst precursor for the Suzuki−Miyaura cross-coupling between alkyl halides and aryl boronic esters was developed, and a protocol for carrying out cross-coupling reactions without the aid of a glovebox was established. Bearing one β-diketiminate ligand and two acetylacetonate ligands, the new iron complex displayed long-term stability in the solid state, as assessed by a combination of ¹H NMR spectroscopy, Mössbauer spectroscopy, and its sustained catalytic activity after being exposed to air for months. We anticipate that this advance will enable the practical implementation of iron-based catalysts for the Suzuki−Miyaura cross-coupling reaction. Considering that the reaction is particularly effective at incorporating alkyl halide substrates and it is compatible with heterocycles commonly observed in pharmaceuticals, we expect that iron-based complexes will provide complementary reactivity to well-established palladium-based catalysts used for the Suzuki−Miyaura cross-coupling of two sp²-hybridized substrates. The low toxicity of iron compared to nickel may also make these catalysts advantageous compared to air-stable nickel-based complexes that have previously been developed for similar reactions.^7–9 Ultimately, we hope that this improved protocol for iron-catalyzed Suzuki−Miyaura cross-coupling reactions paves the way for facile access to previously inaccessible structures that may be useful for structure−activity relationship studies in the pharmaceutical industry.

EXPERIMENTAL SECTION

General Considerations.

Unless stated otherwise, all reactions were carried out in oven-dried glassware in a nitrogen-filled glovebox or using standard Schlenk line techniques.⁴² Solvents including tetrahydrofuran, pentane, and benzene were used after passage through two activated alumina columns under a blanket of argon⁴³ and then degassed by brief exposure to vacuum. Deuterated solvents were dried over a sodium/benzophenone pot and distilled prior to their use. Boronic acid pinacol esters were used after passage through alumina under a nitrogen atmosphere. Methylethylamine was purchased from TCI America; diethylamine was purchased from Sigma-Aldrich. Amines that were liquids at room temperature were dried over calcium hydride for at least 24 h and then distilled under vacuum. Lithium amides were passed through a 250 μm sieve to ensure homogeneous particle size prior to use. Lithium amide salts are pyrophoric when exposed to air, but their flammability is mitigated when they are dissolved in solution. The β-diketiminate ligand used for the synthesis of iron complexes 1 and 3 was synthesized as described previously.³¹ Aryl boronic ester precursors for compounds 5, 8, and 9 were provided by Amgen. Iron(III) chloride was purchased from Sigma-Aldrich and used without further purification. Iron(III) tris(acetoacetone) was purchased from Acros Organics and used without further purification. Alkyl halides were dried over calcium hydride for at least 24 h and then distilled under vacuum prior to their use.

Nuclear magnetic resonance (NMR) spectra were recorded at ambient temperature on Varian vNMRs operating at 400, 500, or 600 MHz for ¹H NMR, at 160 MHz for ¹¹B NMR, and at 125 MHz for {¹H}¹³C NMR. Spectra were referenced using shifts corresponding to solvent residual protic impurities. Boron trifluoride diethyl etherate (BF₃·Et₂O) was used as an external standard for ¹¹B NMR (0.0 ppm). The line listing for NMR spectra of diamagnetic compounds are reported as follows: chemical shift (multiplicity, coupling constant, integration); paramagnetic compounds are reported as follows: chemical shift (peak width at half height, number of protons). All paramagnetic spectra were collected at 25 °C. Solvent suppressed spectra were collected for paramagnetic complexes in THF using the PRESAT macro on the vNMR software. Infrared spectra were recorded on a Bruker α attenuated total reflectance infrared spectrometer. High-resolution mass spectra were obtained at the Boston College Mass Spectrometry Facility on a JEOL AccuTOF DART instrument. Single-crystal X-ray intensity data were measured on a Bruker Kappa Apex Duo diffractometer using a high-brightness IμS copper source with multilayer mirrors. The low-temperature device used is an Oxford 700 series Cryostream system with a temperature range of 80−400 K. An Olympus SZ1145 stereo zoom microscope was used to view and mount crystals. The crystal structure was solved using ShellX. Solution state magnetic moments were obtained following the method described by Evans.⁴⁴ For Mössbauer spectroscopy, solid samples were prepared under an inert atmosphere within a glovebox with a liquid nitrogen fill port to freeze-trap solid samples at 77 K. Samples were loaded into Delrin sample cups and then frozen in liquid nitrogen. Low-temperature ⁵⁷Fe Mössbauer measurements were performed using a Janis SVT-400T N₂ cryostat for analysis at 80 K. Isomer shift values were measured relative to an α-Fe standard at 298 K. All of the Mössbauer spectra were fit using WMoss (See Co.) software. The associated parameter errors in the fit analyses include the following: δ ± 0.02 mm/s, ΔE_Q ± 3%. The multicomponent fit analyses have an associated quantitation error of ±3%. Since only zero-field Mössbauer measurements were performed, all quadrupole splitting parameters reported herein are absolute values.

General Procedure for the Iron-Catalyzed Cross-Coupling Reaction of Aryl Boronic Esters and Alkyl Halides Performed in a Glovebox.

In a nitrogen-filled glovebox, iron complex 3 (14 mg, 0.025 mmol, 10 mol %) and lithium ethylmethyl amide (32 mg, 0.50 mmol, 2.0 equiv) were added to a 7 mL scintillation vial containing a magnetic stir bar. A 1 mL of benzene solution of boronic acid pinacol ester (0.5 mmol, 2.0 equiv) and alkyl halide (0.25 mmol, 1.0 equiv) was added to the stirring vial, followed immediately by benzene (5 mL) and sealing of the reaction vessel. The reaction mixture was allowed to stir vigorously and quickly became homogeneous. After 24 h of stirring, the reaction was quenched with a saturated aqueous solution of ammonium chloride (10 mL). The aqueous phase was washed with dichloromethane (3 × 40 mL), and combined organic phases were dried over sodium sulfate and filtered through celite. Trimethoxybenzene (42 mg, 0.25 mmol) was added as an internal standard before evaporating the solvent in vacuo. A spectroscopic yield was determined by ¹H NMR spectroscopy before the crude product was purified by silica flash column chromatography to give isolated yields.

General Procedure for the Iron-Catalyzed Cross-Coupling Reaction of Aryl Boronic Esters and Alkyl Halides Using Sieved Lithium Amide under Nitrogen on a Schlenk Line.

In a nitrogen-filled glovebox, lithium ethylmethyl amide (32 mg, 0.50 mmol, 2.0 equiv) was weighed out into a two-neck round-bottom flask equipped with a magnetic stir bar and a 180° joint with stopcock. The stopcock was closed, and the flask sealed with a rubber septum and brought out of the glovebox. The apparatus was attached to the Schlenk line, where it was evacuated and purged with nitrogen. Iron complex 3 (14 mg, 0.025 mmol, 10 mol %) was weighed out open to air and then added dry to the reaction vessel under positive nitrogen pressure. A 1 mL of benzene solution of boronic acid pinacol ester (0.5 mmol, 2.0 equiv) and alkyl halide (0.25 mmol, 1.0 equiv) prepared in a separate syringe was then added to the sealed reaction vessel under positive nitrogen pressure, and the reaction mixture diluted to a volume of 7 mL with benzene before being allowed to stir for 24 h at ambient temperature closed to a nitrogen atmosphere. After 24 h, the reaction was quenched with a saturated aqueous solution of ammonium chloride (10 mL). The aqueous phase was washed with dichloromethane (3 × 40 mL), and combined organic phases were dried over sodium sulfate and filtered through celite. Trimethoxybenzene (42 mg, 0.25 mmol) was added as an internal standard before evaporating the solvent in vacuo. A spectroscopic yield was determined by ¹H NMR spectroscopy before the crude product was purified by silica flash column chromatography to give isolated yields.

General Procedure for the Iron-Catalyzed Cross-Coupling Reaction of Aryl Boronic Esters and Alkyl Halides under Nitrogen on a Schlenk Line.

On the Schlenk line, an oven-dried 10 mL Schlenk tube equipped with a stir bar and purged with N₂ was added ethylmethyl amine (31 mg, 45 μL, 0.55 mmol, 2.1 equiv) and anisole (0.5 mL). A solution of n-butyllithium in hexanes (2.5 M, 0.5 mmol, 2.0 equiv) was added to the reaction vessel, whereupon the reaction mixture turned cloudy. The reaction mixture was allowed to stir at ambient temperature for 15 min. Iron complex 3 (14 mg, 0.025 mmol, 10 mol %) was weighed into a round-bottom flask open to air, which was evacuated on the Schlenk line and backfilled with nitrogen. The iron complex was dissolved in benzene (1 mL) and then added simultaneously to the Schlenk tube by syringe with a 1 mL of benzene solution of boronic acid pinacol ester (0.5 mmol, 2.0 equiv) and alkyl halide (0.25 mmol, 1.0 equiv) prepared in a separate syringe. The reaction mixture was diluted to a volume of 7 mL with benzene and then allowed to stir at room temperature closed to a nitrogen atmosphere. After 24 h, the reaction was quenched with a saturated aqueous solution of ammonium chloride (10 mL). The aqueous phase was washed with dichloromethane (3 × 40 mL), and combined organic phases were dried over sodium sulfate and filtered through celite. Trimethoxybenzene (42 mg, 0.25 mmol) was added as an internal standard before evaporating the solvent in vacuo. A spectroscopic yield was determined by ¹H NMR spectroscopy before the crude product was purified by silica flash column chromatography to give isolated yields.

Procedure for the Iron-Catalyzed Cross-Coupling Reaction of Phenyl Boronic Acid Pinacol Ester and Bromocycloheptane Performed Using a Schlenk Line on a 1 g Scale.

On the Schlenk line, to an oven-dried 100 mL Schlenk tube equipped with a stir bar and purged with N₂ was added ethylmethyl amine (745 mg, 1.08 mL, 12.6 mmol, 2.1 equiv.) and anisole (5 mL). A solution of n-butyllithium in hexanes (2.5 M, 12 mmol, 2.0 equiv) was added to the reaction vessel, whereupon the reaction mixture turned cloudy. The reaction mixture was allowed to stir at ambient temperature for 15 min. Iron complex 3 (335.7 mg, 0.6 mmol, 10 mol %) was weighed into a round-bottom flask open to air, which was evacuated on the Schlenk line and backfilled with nitrogen. The iron complex was dissolved in benzene (2 mL) and then added simultaneously to the Schlenk tube by syringe with a 5 mL of benzene solution of phenyl boronic acid pinacol ester (2.45 g, 12 mmol, 2.0 equiv) and bromocycloheptane (1.06 g, 0.82 mL, 6 mmol, 1.0 equiv) prepared in a separate syringe. The reaction mixture turned dark brown and was diluted to a volume of 70 mL with benzene and then allowed to stir at room temperature under a nitrogen atmosphere. After 24 h, the reaction was quenched with a saturated aqueous solution of ammonium chloride (10 mL). The aqueous phase was washed with dichloromethane (3 × 40 mL), and combined organic phases were dried over sodium sulfate and filtered through celite to yield a dark brown oil. The crude product was purified by silica flash column chromatography, eluting with 100% hexane to deliver phenylcycloheptane as a colorless oil (854 mg, 82% yield).

Synthesis of 2,4-Bis[(2,6-dimethylphenyl)imino]-pentane Iron Chloride Complex (1).

To an oven-dried 50 mL round-bottom flask equipped with a stir bar was added 2,4-bis[(2,6-dimethylphenyl)imino]pentane (500 mg, 1.63 mmol, 1.0 equiv) and pentane (25 mL). On the Schlenk line, the mixture was cooled to −78 °C and degassed by placing the solution under vacuum for at least 5 min. A solution of butyllithium in hexanes (0.9 mL, 1.8 M, 1.63 mmol) was added dropwise while stirring. A pale yellow precipitate forms upon warming to ambient temperature. The reaction mixture was warmed to room temperature while stirring before the solvent was removed under vacuum. The sealed reaction vessel was transferred into a glovebox, where the solid was collected on a frit and washed with cold pentane (5 mL at −40 °C). The solid was dried and weighed to determine stoichiometry for the next step. No characterization of the lithium salts of the ligand were carried out. The collected deprotonated ligand (500 mg, 1.6 mmol, 1.0 equiv) was then dissolved in THF (10 mL) in a 20 mL scintillation vial. This solution was added dropwise to a slurry of iron trichloride (260 mg, 1.6 mmol, 1.0 equiv) in THF (10 mL) prepared in a separate scintillation vial equipped with stir bar. This mixture was allowed to stir for 1 h before being placed in a −40 °C refrigerator overnight to precipitate. The reaction mixture was filtered through celite and washed with THF, and then the filtrate was concentrated in vacuo. The residue was washed with cold pentane (10 mL), dried, and collected as a dark yellow solid (450 mg, 45%). Spectral data matched that of the analogous iron(II) dihalide complex.^{31 1}H NMR (400 MHz, THF) δ −68.7 (w_1/2 = 180 Hz, 6H), −52.0 (w_1/2= 100 Hz, 2H), −39.7 (w_1/2 = 264 Hz, 1H), 6.2 (w_1/2 = 254 Hz, 12H), and 16.1 (w_1/2 = 82 Hz, 4H) ppm.

Synthesis of 2,4-Bis[(2,6-dimethylphenyl)imino]-pentane Iron(III) Dichloride (2).

In a nitrogen-filled glovebox, to a 7 mL scintillation vial equipped with a stir bar was added 2,4-bis[(2,6-dimethylphenyl)imino]pentane iron(II) chloride complex (100 mg, 0.17 mmol, 1.0 equiv) and ferrocenium hexafluorophosphate (57 mg, 0.17 mmol, 1.0 equiv). The solids were dissolved in THF (2 mL), at which point the reaction mixture turned a dark purple immediately. The reaction mixture was allowed to stir for 1 h at ambient temperature, and then the solvent evaporated in vacuo. The crude material was subjected to recrystallization from pentane at −40 °C overnight to afford the title compound as a dark purple solid of X-ray quality (25 mg, 66% yield). ¹H NMR (400 MHz, THF, solvent suppressed) δ 68.64 (w_1/2 = 1007 Hz, 12H), 16.12 (w_1/2 = 224 Hz, 2H), −36.25 (w_1/2 = 800 Hz, 4H), −52.01 (w_1/2 = 248 Hz, 1H), and −68.68 (w_1/2 = 335 Hz, 6H). IR: 3357, 1560, 1523, 1473, 1446, 1276, 1193, 843, 773, and 555 cm⁻¹. μ_eff (THF, 25 °C): 6.54 μ_B. HRMS-DART (m/z): [M + H]⁺ calculated for C₂₁H₂₆N₂Cl₂Fe, and 432.19; found, 432.08.

Synthesis of 2,4-Bis[(2,6-dimethylphenyl)imino]-pentane Iron(III) Bis(acetylacetone) (3).

To an oven-dried 100 mL pear-shaped round-bottom flask equipped with a stir bar was added 2,4-bis[(2,6-dimethylphenyl)imino]pentane ligand (4.59 g, 15.0 mmol, 1.05 equiv) and pentane (25 mL). A 180° joint with stopcock was attached, and the apparatus was sealed with a rubber band and copper wire. On the Schlenk line, the mixture was cooled to −78 °C and degassed by placing the solution under vacuum for 5 min. A solution of butyllithium in hexanes (4.75 mL, 3 M, 1 equiv.) was added dropwise via sidearm while stirring at −78 °C. A pale yellow precipitate forms upon warming to ambient temperature. The reaction mixture was allowed to stir 30 min at ambient temperature before the solvent was removed under vacuum. The sealed reaction apparatus was transferred to a glovebox, and the solid was collected on a frit and washed with cold pentane (10 mL). The collected solid was dried and weighed to determine stoichiometry for the next step. The deprotonated ligand (4.56 g, 14.6 mmol, 1 equiv.) was dissolved in THF (5 mL) in a 20 mL scintillation vial. This solution was added dropwise to a suspension of Fe(acac)₃ (5.16 g, 14.6 mmol, 1 equiv.) in THF (5 mL) prepared in a separate scintillation vial equipped with a stir bar. This mixture was allowed to stir overnight, during which time it turned from red-orange to dark green. The reaction mixture was cooled before being passed through celite and then washed with additional THF (∼ 20 mL) before it was concentrated under vacuum. The resulting solid residue was washed with pentane, dried, and collected to afford the product as a dark green solid (4.9 g, 60% yield). ¹H NMR (500 MHz, C₆D₆) δ 42.94 (w_1/2 = 1550 Hz, 4H), 33.09 (w_1/2 = 4136 Hz, 6H), 20.19 (w_1/2 = 1827 Hz, 12H), 15.83 (w_1/2 = 1568 Hz, 8H), −31.79 (w_1/2 = 425 Hz, 3H), and −47.02 (w_1/2 = 1410 Hz, 6H). IR: 2919, 1577, 1520, 1371, 1272, 1020, and 764 cm⁻¹. μ_eff (THF, 25 °C): 7.04 μ_B. HRMS-DART (m/z): [M + H]⁺ calculated for C₃₁H₃₉N₂O₄Fe, 559.51; found, 560.23. Elemental analysis for C₃₁H₃₉N₂O₄Fe: calculated C 66.55%, H 7.03%, and N 5.01%; found C 63.17%, H 6.65%, and N 4.52%. Discrepancies in the elemental analysis are believed to be due to the presence of residual Fe(acac)₃.

Synthesis of 2-Cycloheptyl Thiophene (4).

4 was synthesized from bromocycloheptane and 2-thiophenyl boronic acid pinacol ester according to the general procedure on the Schlenk line, using catalyst 3, and purified by silica gel flash column chromatography, eluting with 100% hexanes to afford the product as a colorless oil (13 mg, 32% spectroscopic yield, 38% based on the recovered starting material, 29% isolated). R_f = 0.75 (100% hexanes). ¹H NMR (400 MHz, CDCl₃): δ 7.07 (d, J = 5.1, 1H), 6.90 (t, J = 5.1, 3.4 Hz, 1H), 6.78 (d, 1H), 3.04 (septet, J = 4.6 Hz, 1H), 2.12−2.03 (m, 1H), 1.81−1.64 (m, 4H), and 1.57−1.48 (m, 5H) ppm. ¹H NMR spectrum is in agreement with literature precedence.³¹

Synthesis of 3-Cycloheptyl Thiophene (5).

5 was synthesized from bromocycloheptane and 3-thiophenyl boronic acid pinacol ester according to the general procedures in the glovebox and on the Schlenk line, using catalyst 3, and purified by silica gel flash column chromatography, eluting with 100% hexanes to afford the product as a colorless oil (23 mg, 53% spectroscopic yield, 58% based on the recovered starting material, 51% isolated). R_f = 0.75 (100% hexanes). ¹H NMR (400 MHz, CDCl₃): δ 7.22 (dd, J = 5.0, 3.0 Hz, 1H), 6.97 (d, J = 5.0 Hz, 1H), 6.91 (s, 1H), 2.82 (septet, J = 9.9, 4.7 Hz, 1H), 1.98 (m, 2H), 1.80−1.72 (m, 2H), and 1.71−1.47 (m, 8H) ppm. The NMR spectrum is in agreement with literature precedence.³¹

Synthesis of (3-(Trifluoromethyl)phenyl) Cycloheptane (6).

6 was synthesized from bromocycloheptane and (3-(trifluoromethyl)phenyl) boronic acid pinacol ester according to the general procedure on the Schlenk line, using catalyst 3, and purified by silica gel flash column chromatography, eluting with 100% hexanes to afford the product as a colorless oil (41 mg, 66% spectroscopic yield, 66% based on the recovered starting material, 68% isolated). R_f = 0.80 (100% hexanes). ¹H NMR (400 MHz, CDCl₃): δ 7.43−7.36 (m, 4H), 2.73 (septet, 1H), l.95−1.86 (m, 2H), 1.86−1.77 (m, 2H), and 1.74−1.51 (m, 8H) ppm. The NMR spectrum is in agreement with literature precedence.²²

Synthesis of 3-Cycloheptyl Furan (7).

7 was synthesized from bromocycloheptane and 3-furyl boronic acid pinacol ester according to the general procedure on the Schlenk line, using catalyst 3, and purified by silica gel flash column chromatography, eluting with 100% hexanes to afford the product as a colorless oil (23 mg, 55% spectroscopic yield, 60% based on the recovered starting material, 56% isolated). R_f = 0.95 (100% hexanes). ¹H NMR (400 MHz, CDCl₃): δ 7.33 (s, 1H), 7.19 (s, 1H), 6.28 (s, 1H), 2.63 (septet, 1H), 1.94 (m, 2H), 1.76−1.62 (m, 4H), and 1.57−1.48 (m, 6H) ppm. The NMR spectrum is in agreement with literature precedence.³¹

Synthesis of 6-Cycloheptyl Quinoline (8).

8 was synthesized from bromocycloheptane and 6-quinolyl boronic acid pinacol ester according to the general procedure on the Schlenk line heated to 50 °C, using catalyst 3, and purified by silica gel flash column chromatography, eluting with 100% hexanes to afford the product as a colorless oil (20 mg, 34% spectroscopic yield, 45% based on the recovered starting material, 36% isolated). R_f = 0.45 (30% ethyl acetate in hexanes). ¹H NMR (400 MHz, CDCl₃): δ 8.85 (d, J = 4.1 Hz, 1H), 8.13 (d, J = 8.3 Hz, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.63−7.55 (m, 2H), 7.45−7.36 (m, 1H), 2.88i (septet, 1H), 2.04−1.95 (m, 2H), 1.89−1.79 (m, 2H), 1.79−1.71 (m, 4H), and 1.71−1.57 (m, 4H) ppm. The NMR spectrum is in agreement with literature precedence.³¹

Synthesis of 6-(4-Boc-piperazin-1-yl)-3-cycloheptyl Pyridine (9).

9 was synthesized from bromocycloheptane and 6-(4-boc-piperazin-1-yl)pyridine-3-boronic acid pinacol ester according to the general procedure on the Schlenk line heated to 50 °C, using catalyst 3, and purified by silica gel flash column chromatography, eluting with 100% hexanes to afford the product as a colorless oil (65 mg, 72% spectroscopic yield, 72% based on the recovered starting material, 72% isolated). R_f = 0.45 (30% ethyl acetate in hexanes). ¹H NMR (400 MHz, CDCl₃): δ 8.04 (s, 1H), 7.37 (m, 1H), 6.59 (m, 1H), 3.53 (m, 4H), 3.46 (m, 4H), 2.59 (septet, 1H), 1.89−1.81 (m, 2H), 1.81−1.73 (m, 2H), 1.72−1.65 (m, 2H), 1.65−1.51 (m, 6H), and 1.48 (s, 9H) ppm. The NMR spectrum is in agreement with literature precedence.³¹

Synthesis of (4-Methoxyphenyl) Cycloheptane (10).

10 was synthesized from bromocycloheptane and (4-methoxy-phenyl) boronic acid pinacol ester according to the general procedure on the Schlenk line, using catalyst 3, and purified by silica gel flash column chromatography, eluting with 100% hexanes to afford the product as a white solid (18 mg, 34% spectroscopic yield, 43% based on the recovered starting material, 35% isolated). R_f = 0.60 (10% ethyl acetate in hexanes). ¹H NMR (500 MHz, CDCl₃): δ 7.11 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 2.61 (septet, J = 10.3, 5.1 Hz, 1H), 1.94−1.82 (m, 2H), 1.82−1.72 (m, 2H), 1.72−1.64 (m, 2H), and 1.64−1.49 (m, 6H) ppm. The NMR spectrum is in agreement with literature precedence.²²

Synthesis of Phenyloctane (11).

11 was synthesized from bromooctane and phenyl boronic acid pinacol ester according to the general procedure on the Schlenk line, using catalyst 3, and purified by silica gel flash column chromatography, eluting with 100% hexanes to afford the product as a colorless oil (19 mg, 39% spectroscopic yield, 60% based on the recovered starting material, 40% isolated). R_f = 0.60 (100% hexanes). ¹H NMR (400 MHz, CDCl₃): δ 7.27 (m, 2H), 7.18 (d, J = 7.2 Hz, 3H), 2.60 (t, J = 7.5 Hz, 2H), 1.65−1.57 (m, 2H), 1.32−1.26 (m, 10H), and 0.90−0.86 (m, 3H) ppm. The NMR spectrum is in agreement with literature precedence.³¹

Synthesis of Phenylcyclobutane (12).

12 was synthesized from bromocyclobutane and phenyl boronic acid pinacol ester according to the general procedure on the Schlenk line, using catalyst 3, and purified by silica gel flash column chromatography, eluting with 100% hexanes to afford the product as a colorless oil (10 mg, 34% spectroscopic yield, 34% based on the recovered starting material, 31% isolated). R_f = 0.70 (100% hexanes). ¹H NMR (400 MHz, CDCl₃): δ 7.33−7.14 (m, 5H), 3.56 (p, J = 8.8 Hz, 1H), and 2.40−1.81 (m, 6H) ppm. The NMR spectrum is in agreement with literature precedence.³¹

Synthesis of Phenylcyclopropane (13).

13 was synthesized from bromocyclopropane and phenyl boronic acid pinacol ester according to the general procedure on the Schlenk line, using catalyst 3, and purified by silica gel flash column chromatography, eluting with 100% hexanes to afford the product as a colorless oil (8 mg, 27% spectroscopic yield, 27% based on the recovered starting material, 27% isolated). R_f = 0.75 (100% hexanes). ¹H NMR (400 MHz, CDCl₃) δ 7.47 (d, J = 7.4 Hz, 2H), 7.14 (t, J = 7.5 Hz, 1H), 7.09 (d, J = 7.8 Hz, 2H), 1.91 (m, 1H), 0.97 (q, J = 8.4 Hz, 2H), and 0.71 (q, J = 4.6 Hz, 2H) ppm. The NMR spectrum is in agreement with literature precedence.³¹

Synthesis of Phenylcycloheptane (14).

14 was synthesized from bromocycloheptane and phenyl boronic acid pinacol ester according to the general procedures in the glovebox and on the Schlenk line, using catalyst 3, and purified by silica gel flash column chromatography, eluting with 100% hexanes to afford the product as a colorless oil (13 mg, 32% spectroscopic yield, 38% based on recovered starting material, 29% isolated). R_f = 0.60 (100% hexanes). ¹H NMR (500 MHz, CDCl₃): δ 7.23−7.33 (m, 2H), 7.08−7.23 (m, 2H), 2.66 (tt, J = 10.7, 3.7 Hz, 1H), 1.92 (ddt, J = 13.5, 6.6, 3.3 Hz, 2H), 1.80 (ddd, J = 13.4, 6.6, 3.4 Hz, 2H), and 1.46−1.78 (m, 8H) ppm. The NMR spectrum is in agreement with literature precedence.²²

Synthesis of tert-Butyl Benzene (15).

15 was synthesized from tert-butyl chloride and phenyl boronic acid pinacol ester according to the general procedure on the Schlenk line, using catalyst 3, and purified by silica gel flash column chromatography, eluting with 100% hexanes to afford the product as a colorless oil (21 mg, 63% isolated). R_f = 0.60 (100% hexanes). ¹H NMR (400 MHz, CDCl₃) δ 7.84−7.78 (m, 2H), 7.48−7.42 (m, 1H), 7.37 (t, J = 7.4 Hz, 2H), and 1.35 (s, 9H) ppm. The NMR spectrum is in agreement with literature precedence.³¹

Synthesis of Adamantylbenzene (16).

16 was synthesized from chloroadamantane and phenyl boronic acid pinacol ester according to the general procedure on the Schlenk line, using catalyst 3 and purified by silica gel flash column chromatography, eluting with 100% hexanes to afford the product as a white solid (22 mg, 41% isolated). R_f = 0.60 (100% hexanes). ¹H NMR (500 MHz, CDCl₃): δ 7.2−7.4 (m, 5H), 2.10 (m, 3H), 1.92 (m, 6H), and 1.77 (m, 6H) ppm. The NMR spectrum is in agreement with literature precedence.³¹

Synthesis of 4-Phenylpiperidine-1-carboxylic Acid Benzyl Ester (17).

17 was synthesized from 4-bromopiperidine-1-carboxylic acid benzyl ester and phenyl boronic acid pinacol ester according to the general procedure on the Schlenk line, using catalyst 3, and purified by silica gel flash column chromatography, eluting with 100% hexanes to afford the product as a colorless oil (20 mg, 31% spectroscopic yield, 45% based on the recovered starting material, 27% isolated). R_f = 0.20 (15% ethyl acetate in hexanes). ¹H NMR (500 MHz, CDCl₃): δ 7.40−7.26 (m, 7H), 7.23−7.17 (m, 3H), 5.16 (s, 2H), 4.34 (br s, 2H), 2.89 (m, 2H), 2.67 (tt, J = 12.0, 3.2 Hz, 1H), 1.85 (d, J = 13.2 Hz, 2H), and 1.70−1.61 (m, 2H) ppm. The NMR spectrum is in agreement with literature precedence.³¹

Synthesis of tert-Butyldimethyl((9-phenyldecyl)oxy)-silane (18).

18 was synthesized from tert-butyldimethyl((9-bromodecyl)oxy)silane and phenyl boronic acid pinacol ester according to the general procedure on the Schlenk line, using catalyst 3, and purified by silica gel flash column chromatography, eluting with 100% hexanes to afford the product as a colorless oil (43 mg, 48% spectroscopic yield, 48% based on recovered starting material, 49% isolated). R_f = 0.15 (100% pentane). ¹H NMR (500 MHz, CDCl₃): δ 7.32−7.26 (m, 2H), 7.20−7.10 (m, 3H), 3.58 (m, 2H), 2.67 (q, J = 7.1 Hz, 1H), 1.58−1.54 (m, 2H), 1.51−1.45 (m, 2H), 1.34−1.19 (m, 13H), 1.18−1.11 (m, 2H), 0.90 (s, 9H), and 0.04 (s, 6H) ppm. The NMR spectrum is in agreement with literature precedence.³¹

Synthesis of 5-Phenylpentyl Cyanide (19).

19 was synthesized from 5-bromopentyl cyanide and phenyl boronic acid pinacol ester according to the general procedure on the Schlenk line, using catalyst 3, and purified by silica gel flash column chromatography, eluting with 100% hexanes to afford the product as a colorless oil (9 mg, 18% spectroscopic yield, 18% based on the recovered starting material, 20% isolated). R_f = 0.15 (5% ethyl acetate in hexanes). ¹H NMR (400 MHz, CDCl₃): δ 7.28 (t, J = 7.4 Hz, 2H), 7.20−7.14 (m, 3H), 2.62 (t, J = 7.5 Hz, 2H), 2.33 (t, J = 7.0 Hz, 2H), 1.74−1.51 (m, 4H), and 1.56−1.43 (m, 2H) ppm. The NMR spectrum is in agreement with literature precedence.⁴⁵