Suzuki-Miyaura Cross-Coupling of Potassium Alkoxyethyltri-fluoroborates: Access to Aryl/Heteroarylethyloxy Motifs

Abstract

The introduction of an alkoxyethyl moiety onto aromatic substructures has remained a long-standing challenge for synthetic organic chemists. The main reasons are the inherent instability of alkoxyethylmetallic species and the lack of general procedures to access them. A new method utilizing a cross-coupling strategy based on the exceptional properties of organotrifluoroborates has been developed, and the method allows an easy and efficient installation of this unit on a broad range of aryl and heteroaryl bromides.

INTRODUCTION

The Suzuki-Miyaura reaction has become a predominant asset in the toolbox of chemical transformations regularly employed by organic chemists.¹ Among the metal-catalyzed carbon-carbon bond forming reactions, this cross-coupling reaction between a boron species and an electrophile has gained dramatic interest owing to its robustness, versatility, and the relative lack of toxicity of its generated by-products.

Our research group has devoted its efforts toward the development of organotrifluoroborates as new and efficient boron coupling partners.² Their tetracoordinate nature confers increased stability upon them, and when placed in specific reaction conditions, they slowly release in situ the reactive boron species that can undergo the desired cross-coupling reaction.³ These unique features make them highly useful, functional group tolerant, bench-stable reagents that perform very well in the Suzuki-Miyaura reaction. Based on these properties, it has been possible to synthesize and cross-couple a large array of functionalized methyltrifluoroborates such as alkoxymethyl-, aminomethyl-, amidomethyl-, and carbamatomethyltrifluoroborates, providing new and useful methods to access those motifs.^{2e, 4}

To complement those useful synthons, our attention had been drawn to the development of alkoxyethyltrifluoroborates as an unprecedented way to synthesize alkoxyethylarenes. The current common methods to introduce the alkoxyethyl moiety are limited to reaction sequences such as the addition of an organometallic reagent to ethylene oxide or 2-haloethers, or hydroboration/oxidation/alkylation of a styrene derivative. Aside from requiring several steps, these routes suffer from harsh reaction conditions, low yields, as well as sensitivity/toxicity and poor availability of the reagents, all of which greatly limit their general application. A cross-coupling strategy would dramatically improve this situation and make the introduction of the alkoxyethyl group a very simple and straightforward process.

However, this concept is ultimately based on the ability to synthesize alkoxyethylboron coupling partners, several potential routes to which are depicted in Scheme 1. In general, these routes are fraught with challenges. Indeed, it is well documented that halogenoethyl-boron compounds are unstable.⁵ For instance, β-bromoethylboronate species experience facile deboronobromination in the presence of weak nucleophiles such as potassium cyanate, aniline, pyridine, or even water.^5b The mechanism of the decomposition, yielding ethylene and boron byproducts, transpires through a concerted anti elimination pathway that can be triggered by a Lewis base.⁶ On the other hand, the hydroboration of vinyl ethers, products of which are a bit more stable depending on the steric hindrance on the boron atom,⁷ is not a suitable route either, as the intermediates are prone to transfer and elimination reactions.⁸ Elimination can proceed through a syn or an anti mechanism depending on the presence or absence of a Lewis acid. Another synthetic pathway would employ the use of an alkoxyethylor-ganometallic species (such as organomagnesium or organolithium species) reacting with a borate, but unfortunately, such organometallic species are not stable and tend to decompose rapidly.⁹

Scheme 1.

Potential Synthetic Routes to Alkoxyethylboron Species.

RESULTS AND DISCUSSION

Given that the desired alkoxyethylboron compounds were not easily accessible, their use as reagents remained on hold until the development of metal-catalyzed borylation reactions. In 2004, Hartwig reported the synthesis of an alkoxyethyl pinacolboronate via a Rh-catalyzed borylation of an ethyl ether with bis(pinacolato)diborane followed by its subsequent cross-coupling with an aryl bromide or hydrolysis of the boronate to a trifluoroborate.¹⁰ Unfortunately, besides being run on very small scale (0.14 mmol in NMR tubes) without isolation of the products (GC and NMR yields), the reaction conditions, which require a 10 fold excess of ethyl ether and heating the reaction mixture at 150 °C for 24 h, were not suitable for a large variety of substrates.

More recently, and in a very short time period, the borylation of non-activated alkyl halides has attracted much interest in the chemical community.¹¹ Several research groups have developed mild reactions conditions (rt to 60 °C) based on copper, nickel or palladium catalysis. Although they all possess wide functional group tolerability, only two examples of alkoxyethylboron derivatives have been reported via one of these methods.^11a,b,c Our attention was focused on the method developed by Marder and Liu as it relies on the use of inexpensive PPh₃ and copper(I).^11a A few modifications of the reaction conditions allowed us to synthesize various alkoxyethyltrifluoroborates. In particular, the use of polystyrene-supported triphenylphosphine (PS-PPh₃) as mentioned in the original report improved both the efficiency and the yield of the process, as various alkoxyethyltrifluoroborates could be prepared by addition of KHF₂ to the reaction mixture after the borylation step, avoiding contamination by triphenylphosphine oxide.¹² The different alkoxyethyltrifluoroborates prepared in this manner are summarized in Scheme 2.

Scheme 2.

Synthesis of Alkoxyethyltrifluoroborates via a Copper Catalyzed Borylation Procedure.

The desired alkoxyethyltrifluoroborates were obtained with moderate to good yields (24–68%) and are all white powders that showed no sign of decomposition after several months being stored on the bench with no particular precautions. The borylation procedure tolerates a wide variety of functional groups on the oxygen such as alkyl, benzyl or aryl substituents (yields of 1a-d ranging from 55 to 68%). However, more sensitive substrates provided lower yields, as illustrated by the acetoxyethyltrifluoroborate 1f and the silyl ether derivative 1i, which were obtained in 40 and 43% yields, respectively. Cyclic secondary alkoxyethyl bromides did not react as well, and the corresponding trifluoroborates (1g, 1h) were isolated in slightly lower yields. Attempts at using the Ni based procedure reported by Fu et al., which was developed for unactivated tertiary halides, did not provide better results. It is interesting to note that bromoethyl ethers bearing various easily removable protecting groups, such as benzyl, acetate, THP or TBDPS could be utilized, and thus would easily provide access to a free hydroxyl group for further functionalization after the Suzuki-Miyaura coupling step.¹³

Direct conversion of the boronate esters to the corresponding potassium trifluoroborates helped to solve some stability issues of the alkoxyethylboron derivatives.¹⁴ Even if the alkoxyethylpinacolatoborons are more stable than their boronic acid counterparts, they still remain sensitive and prone to decomposition. The benzyloxyethyltrifluoroborate 1c could be recrystallized, and its X-ray structure was elucidated (Figure 1). Notably, the potassium cation can be seen bridging the oxygen and one of the fluorine atoms, rigidifying the structure of the molecule. A comparative study on the rate of degradation of an alkoxyethyltrifluoroborate has been conducted. It showed that in the presence of 18-crown-6, the trifluoroborate degrades faster, suggesting an important role of the potassium ion in stabilizing the complexes.¹⁵

Figure 1.

X-ray Structure of Potassium Benzyloxyethyltrifluoroborate 1c.

Extensive screening using High Throughput Experimentation (HTE) techniques allowed us to define efficient conditions to perform the Suzuki-Miyaura cross-coupling of the benzyloxyethyltrifluoroborate 1c and various aryl bromides (Table 1). The best catalytic system was found to be PdCl₂A^taPhos₂ in the presence of cesium carbonate in toluene/water at 100 °C. This di-tert-butyl(4- dimethylamino)phenylphosphine was developed in 2006 by Guram et al.¹⁶ and showed very interesting results in Suzuki-Miyaura cross-coupling reactions, especially when used as the air stable PdCl₂L₂ complex.^15,17 The steric and electronic properties of this ligand seem to help reduce β-hydride elimination when compared to P(t-Bu)₃,¹⁸ and the ligand has been shown to provide very good results in the cross-coupling of alkyl α-cyanohydrin triflates with arylboronic acids.^16c

Table 1.

Suzuki Cross-Coupling of Benzyloxyethyltrifluoroborate 1c and Various Aryl Bromides.^a

entry	product	isolated yield (%)b
1	2a	82 30% conv.(Cl)
2	2b	92
3	2c	93
4	2d	51
5	2e	82
6	2f	93c
7	2g	74
8	2h	89
9	2i	76d
10	2j	89
11	2k	77
12	2l	82 88 (Cl)
13	2m	67
14	2n	74 57 (Cl)
15	2o	82
16	2p	92
17	2q	93
18	2r	87
19	2s	72e

^aGeneral conditions: aryl bromide/chloride (0.25 mmol), trifluoroborate (0.275 mmol), Cs₂CO₃ (0.75 mmol) in toluene (1 mL)/H₂O (0.25 mL) at 100 °C for 24 h

^bIsolated yield after purification by flash chromatography on silica gel or recrystallisation

^cReaction performed on a 3 mmol scale using 2.5 mol % catalyst

^dProduct contains up to 8% impurity

^eReaction performed on a 3 mmol scale using a 1 : 1 trifluoroborate/electrophile ratio and 1 mol % Pd.

As shown in Table 1, the substrate scope of the reaction between benzyloxyethyltrifluoroborate 1c and aryl bromides is very broad. The reaction conditions seem to be extremely general as they allow both electron rich (entries 1–8) and electron poor (entries 9–19) bromides to be coupled with very good results. Electron donating groups are tolerated on all positions of the aryl bromide, as illustrated by the ortho, meta, and para-bromoanisoles, affording the desired benzyloxyethylanisole derivatives with yields ranging from 82 to 93% (entries 1–3). Electron withdrawing substituents at the para position seem to provide better results than at the ortho position (entries 9, 10 and 12, 13). Steric hindrance might not be the factor responsible for this observed trend as other mono- or di-substituted electrophiles (entries 5,6) cross-coupled efficiently with excellent yields (93 and 82%, respectively). The conditions are applicable to a large variety of functional groups such as aldehydes (entry 14), ketones (entry 15), esters (entry 16), nitriles (entries 12–13), nitro (entry 17), and even amides and sulfonamides (entries 18–19).

The robustness of the method was tested by performing the reaction on a larger scale (3 mmol of electrophile, entries 9 and 18). When using ortho-tolyl bromide, the cross coupling product was obtained with an excellent 93% isolated yield, even after reducing the catalyst loading to 2.5 mol %. para-Acetamidobenzyl bromide was also tested on a larger scale and provided the expected cross-coupled product 2r in a slightly lower yield (78%) after recrystallization (hexanes/ethyl acetate) when using only 1 mol % palladium and a 1:1 trifluorobo-rate/electrophile ratio. The reaction conditions were also tested with several aryl chlorides with less success. Electron-rich chlorides such as para-chloroanisole failed to react efficiently (30% conversion, entry 1), whereas electron-poor substrates cross-coupled smoothly, providing the desired benzyloxyethylbenzene derivatives with moderate to excellent yields (entries 12, 14).

The scope of the method was then further extended to heteroaryl bromides using the same set of optimized conditions. They proved to be effective, resulting in yields up to 89% for a wide array of heteroaryls. 3-Bromopyridines with or without substituents afforded the desired products in moderate to good yields (entries 1–2). Quinoline and isoquinoline also responded well to the reaction conditions, coupling with yields up to 83% (entries 4–5). Indole-based electrophiles were also reactive; however, better yields were obtained when the nitrogen was protected (89% vs 55%, entries 6, 7). Pyrimidine, which is a particularly difficult substrate, was cross-coupled efficiently to give the corresponding product 3h in 69% yield. 5-Membered heterocycles were also tolerated; 3-bromothiophene gave the expected product 3i in 88% yield (entry 9). 2-Halopyridines were also engaged in the reaction and could be cross-coupled, albeit in much lower yield (entry 3). Interestingly, the chloropyridine reacted better than its bromo-counterpart owing to its lower tendency to undergo homocoupling.

The versatility of this new method was then demonstrated by employing different alkoxyethyltrifluoroborates as coupling partners under the same conditions (Table 3). Alkyl-substituted trifluoroborates provided the desired cross-coupled products in moderate to good yields (entries 1–3, 5–6), while the phenoxyethyl derivative 1d afforded the expected product 4d in only 31% yield. This substrate showed higher reactivity, as numerous by-products were observed after the reaction (Heck, dimer, degradation…). It is interesting to note that for several substrates the yields could be improved by lowering the reaction temperature to 85 °C (entries 2, 6). Secondary alkoxyethyltrifluoroborates also proved to be suitable partners, providing yields up to 70% (entries 5–6). Trifluoroborates bearing more sensitive functional groups such as a silyl ether or an acetate moiety failed to give the cross-coupled products under the reaction conditions. When trifluoroborate 1i (entry 7) was used, the corresponding silanol and bromoanisole were retrieved after the reaction, suggesting that the fluoride ions released during the hydrolysis of the trifluoroborate salt caused the cleavage of the silyl group and led to degradation before the cross-coupling could take place. The acetate group has been reported not to survive the reaction conditions;¹⁹ however, the deprotected coupled product was not detected either, even when using milder reaction conditions.

Table 3.

Suzuki Cross-Coupling of Various Alkoxyethyltrifluoroborates and para-Bromoanisole.^a

entry	trifluoroborate	product	isolated yield (%)b
1		4a	63c
2		4b	72 88d
3		4c	77
4		4d	31
5		4e	70
6		4f	49 60d
7		4g	0
8		4h	0e

^aGeneral conditions: 4-bromoanisole (0.25 mmol), trifluoroborate (0.275 mmol), Cs₂CO₃ (0.75 mmol) in toluene (1 mL)/H₂O (0.25 mL) at 100 °C for 24 h

^bIsolated yield after purification by flash chromatography on silica gel

^cContaminated by 7% impurity

^dReaction performed at 85 °C

^eReaction also performed at 85 °C in 10:1 toluene/H₂O and 2 equiv of base.

CONCLUSIONS

In summary, a robust and efficient method for the introduction of ethyloxy motifs based on a Suzuki-Miyaura cross-coupling of the alkoxyethyltrifluoroborates has been developed. These coupling partners are synthesized using an inexpensive copper catalyzed borylation reaction. The scope of the method has been studied and includes aryl and heteroaryl bromides. Depending on the functional group on the alkoxyethyl unit, the resulting compounds can easily be deprotected to the corresponding alcohols.²⁰ This method is based on the unique properties offered by the trifluoroborates salts, as well as the versatility of the Suzuki-Miyaura reaction, and provides a novel, complementary means to generate alkoxyethylarenes that takes advantage of the wide availability of aryl halides as synthetic partners in the cross-coupling reaction.

EXPERIMENTAL SECTION

General Considerations

All commercially available reagents were used without purification. Both solvents and deionized water were degassed with N₂ each time prior to use. Standard benchtop techniques were employed for handling air-sensitive reagents. Melting points (°C) are uncorrected. NMR spectra were recorded on a 500, 400, or 300 MHz spectrometer. The resonance of the carbon center linked to the boron atom was not observed. ¹⁹F NMR chemical shifts were referenced to external CFCl₃ (0.0 ppm). ¹¹B NMR spectra were obtained on a spectrometer equipped with the appropriate decoupling accessories. All ¹¹B NMR chemical shifts were referenced to external BF₃·OEt₂ (0.0 ppm) with a negative sign indicating an upfield shift. Data are presented as follows: chemical shift (ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, br = broad), coupling constant J (Hz) and integration. Analytical thin-layer chromatography (TLC) was performed on TLC silica gel plates (0.25 mm) precoated with a fluorescent indicator. Standard flash chromatography procedures were followed using 32–63 μm silica gel. Visualization was effected with ultraviolet light, KMnO₄ or ceric ammonium molybdate.

General procedure for the preparation of potassium alkoxyethyltrifluoroborates

This procedure was adapted from the borylation procedure reported by Marder and Liu:^11a in air, bis(pinacolato)diboron (1.5 equiv), Li- OMe (2.0 equiv), triphenylphosphine polymer-bound (13 mol %) and CuI (99.999%, 10 mol %) were weighed in a round-bottomed flask equipped with a stir bar. The flask was closed with a septum, evacuated, and backfilled with N₂. DMF (25 mL, c = 0.2 M) and alkoxyethyl bromide (1.0 equiv) was successively added by syringes (or, if the alkoxyethyl bromide was solid, it was added as a solution in DMF), and the resulting mixture was vigorously stirred at rt for 20 h. The reaction mixture was then diluted with CH₂Cl₂ (25 mL) and filtered through a pad of Celite, then rinsed with CH₂Cl₂ (2x50 mL). The resulting soln was concentrated, poured into sat. aq NH₄Cl (50 mL) and extracted with Et₂O (2x50 mL). The combined organic layers were washed successively with H₂O (300 mL) and brine (50 mL), dried (MgSO₄) and concentrated. The residue was solubilized in THF (25 mL) in a round-bottomed flask equipped with a stir bar and sat. aq KHF₂ (4.0 equiv) was added. The flask was closed with a septum and the resulting mixture was stirred 2 h at rt. The reaction mixture was evaporated to dryness, and the resulting salt was extracted several times with hot acetone (5x50 mL). The filtrate was concentrated to ~5 mL, and pre- cipitation was achieved by dropwise addition of Et₂O (60 mL) at 0 °C. The resulting product was collected by gravity filtration on a fritted funnel and dried to the corresponding potassium alkoxyethyltrifluoroborate as a white solid.

Potassium (2-Methoxyethyl)trifluoroborate 1a: following the general procedure, the reaction performed with 2-bromoethyl methyl ether (730 mg, 5.32 mmol) afforded 576 mg (65–68%) of the title compound. mp = 123–125 °C. ¹H NMR (acetone-d⁶, 400 MHz): δ 3.40–3.36 (m, 2H), 3.18 (s, 3H), 0.62–0.43 (m, 2H).¹³C NMR (acetone-d⁶, 100 MHz):δ 73.7, 57.6. ¹¹B NMR (acetone-d⁶, 128 MHz): 4.90 (br s). ¹⁹F NMR (acetone-d⁶, 377 MHz):δ -139.8. IR: ν 2904, 1105, 1060, 1009, 984, 916, 608 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₃H₇BOF₃ (M –K)⁻ 127.0542, found 127.0547.

Potassium (2-Ethoxyethyl)trifluoroborate 1b: following the general procedure, the reaction performed with 2-bromoethyl ethyl ether (678 mg, 3.99 mmol) afforded 488 mg (68%) of the title compound. mp = 112–114 °C.¹H NMR (acetone-d⁶, 400 MHz):δ 3.44–3.38 (m, 2H), 3.34 (q, J=7.0 Hz, 2H), 1.08 (t, J = 7.0 Hz, 3H), 0.59–0.46 (m, 2H). ¹³C NMR (acetone-d⁶, 100 MHz):δ 71.1, 65.5, 15.8. ¹¹B NMR (acetone-d⁶, 128 MHz)δ 4.91 (br s). ¹⁹F NMR (acetone-d⁶, 377 MHz):δ -139.9. IR: ν 2872, 1251, 1069, 1041, 938, 884, 732 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₄H₉BOF₃ (M – K)⁻ 141.0699, found 141.0704.

Potassium (2-Benzyloxyethyl)trifluoroborate 1c: following the general procedure, the reaction performed with 2-bromoethyl benzyl ether (1.09 g, 5.06 mmol) afforded 755 mg (62%) of the title compound. mp = 180–184 °C. ¹H NMR (acetone-d⁶, 400 MHz):δ 7.35–7.27 (m, 4H), 7.22 (tt, J = 6.4, 1.8 Hz, 1H), 4.41 (s, 2H), 3.55–3.51 (m, 2H), 0.65–0.59 (m, 2H). ¹³C NMR (acetone-d⁶, 100 MHz):δ 141.3, 128.9, 128.2, 127.7, 72.4, 71.6. ¹¹B NMR (acetone-d⁶, 128 MHz)δ 4.81 (br s). ¹⁹F NMR (acetone-d⁶, 377 MHz):δ -139.8. IR: 2867, 1328, 1076, 977, 914, 692 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₉H₁₁BOF₃ (M – K)⁻ 203.0855, found 203.0863.

Potassium (2-Phenyloxyethyl)trifluoroborate 1d: following the general procedure, the reaction performed with 2-phenoxyethyl bromide (1.00 g, 4.97 mmol) afforded 621 mg (55%) of the title compound. mp >200 °C. ¹H NMR (acetone-d⁶, 400 MHz):δ 7.22–7.18 (m, 2H), 6.85–6.83 (m, 2H), 6.79 (tt, J = 7.3, 1.0 Hz, 1H), 4.03–3.99 (m, 2H), 0.76–0.71 (m, 2H). ¹³C NMR (acetone-d⁶, 100 MHz):δ 161.1, 130.0, 120.1, 115.4, 69.3. ¹¹B NMR (acetone-d⁶, 128 MHz):δ 4.51 (br s). ¹⁹F NMR (acetone-d⁶, 377 MHz):δ -140.2. IR: ν 1491, 1224, 1082, 1006, 940, 762 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₈H₉BOF₃ (M – K)⁻ 189.0699, found 189.0701.

Potassium (2-(Tetrahydro-2H-pyran-2-yloxy)ethyl)trifluoroborate 1e: following the general procedure, the reaction performed with 2-(2-bromoethoxy)tetrahydro-2H-pyran (2.77 g, 13.2 mmol) afforded 1.96 g (63%) of the title compound. mp = 182–185 °C. ¹H NMR (DMSO-d⁶, 400 MHz):δ 4.45–4.43 (m, 1H), 3.75–3.72 (m, 1H), 3.60–3.55 (m, 1H), 3.36–3.34 (m, 1H), 3.28–3.22 (m, 1H), 1.72–1.68 (m, 1H), 1.58–1.54 (m, 1H), 1.43–1.35 (m, 4H), 0.43–0.26 (m, 2H). ¹³C NMR (DMSO-d⁶, 100 MHz):δ 97.5, 67.7, 61.3, 30.8, 25.3, 19.7. ¹¹B NMR (DMSO-d⁶, 128 MHz):δ 4.28 (br s). ¹⁹F NMR (DMSO-d⁶, 377 MHz):δ -136.0. IR: ν. 2938, 1250, 1070, 1026, 945, 878, 648 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₇H₁₃BO₂F₃ (M – K)⁻ 197.0961, found 197.0960.

Potassium 2-(Trifluoroborato)ethyl acetate 1f: following the general procedure, the reaction performed with 2-bromoethyl acetate (756 mg, 4.53 mmol) afforded 348 mg (40%) of the title compound. mp = 165–167 °C. ¹H NMR (acetone-d⁶, 400 MHz):δ 4.09–4.05 (m, 2H), 1.89 (s, 3H), 0.57–0.54 (m, 2H). ¹³C NMR (acetone-d⁶, 100 MHz):δ 171.5, 67.1, 21.4. ¹¹B NMR (acetone-d⁶, 128 MHz):δ 4.35 (q, J = 63 Hz). ¹⁹F NMR (acetone-d⁶, 377 MHz):δ -140.4. IR: ν 1728, 1244, 1065, 1038, 975, 901, 835 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₄H₇BO₂F₃ (M – K)⁻ 155.0491, found 155.0494.

Potassium ((Tetrahydro-2H-pyran-2-yl)methyl)trifluoroborate 1g: following the general procedure, the reaction performed with 2-(bromomethyl)tetrahydro-2H-pyran (2.79 g, 15.60 mmol) afforded 759 mg (24%) of the title compound, using a Soxhlet apparatus overnight for the hot acetone extraction. mp > 200 °C. ¹H NMR (DMSO-d⁶, 400 MHz):δ 3.73–3.69 (m, 1H), 3.25–3.11 (m, 2H), 1.82–1.79 (m, 1H), 1.66–1.62 (m, 1H), 1.36–1.29 (m, 3H), 0.93–0.90 (m, 1H), 0.35–0.33 (m, 1H), 0.16–0.11 (m, 1H). ¹³C NMR (DMSO-d⁶, 100 MHz):δ 78.4, 67.0, 33.3, 26.3, 23.8. ¹¹B NMR (DMSO-d⁶, 128 MHz):δ = 4.13 (br s). ¹⁹F NMR (DMSO-d⁶, 377 MHz): d -134.4. IR: ν 2925, 1266, 1077, 1031, 950, 880, 722 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₆H₁₁BOF₃ (M – K)⁻ 167.0855, found 167.0856.

Potassium 2-Trifluoroboratomethyl-1,4-benzodioxane 1h: following the general procedure, the reaction performed with 2-bromomethyl-1,4-benzodioxane (3.06 g, 13.38 mmol) afforded 1.26 g (37%) of the title compound. mp > 200 °C. ¹H NMR (acetone-d⁶, 400 MHz):δ 6.75–6.69 (m, 4H), 4.48 (dd, J = 11.3, 2.1 Hz, 1H), 4.16–4.09 (m, 1H), 3.64 (dd, J = 11.3, 8.5 Hz, 1H), 0.87–0.81 (m, 1H), 0.53–0.42 (m, 1H). ¹³C NMR (acetone-d⁶, 100 MHz):δ 146.0, 144.9, 121.5, 120.9, 117.9, 117.4, 75.5, 70.9. ¹¹B NMR (acetone-d⁶, 128 MHz):δ 4.30 (br s). ¹⁹F NMR (acetone-d⁶, 377 MHz):δ -138.6. IR: ν 1594, 1495, 1255, 1036, 939, 897, 751 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₉H₉BO₂F₃ (M – K)⁻ 217.0648, found 217.0648.

Synthesis of Potassium {2-[(tert-Butyldiphenylsilyl)oxy]ethyl}trifluoroborate

(2-Bromoethoxy)(tert-butyl)diphenylsilane:²¹ freshly distilled 2-bromoethanol (881 mg, 7.05 mmol, 1 equiv), was added to a soln of imidazole (1. 2 g, 2.5 equiv) and tert-butyldiphenylsilyl chloride (2.3 g, 1.2 equiv) in DMF (5 mL) according to Corey’s procedure.²² The resulting soln was stirred at rt for 24 hours, treated with H₂O (10 mL) and extracted with EtOAc (3 x 10 mL). The organic layers were combined, dried (MgSO₄), and the solvent was removed under vacuum. The crude material was then purified by flash column chromatography on silica gel using hexanes/EtOAc as eluent to give 1.53 g of a colorless oil (60%). ¹H NMR (CDCl₃, 500 MHz):δ 7.70–7.68 (m, 4H), 7.45–7.39 (m, 6H), 3.94 (t, J = 6.5 Hz, 2H), 3.44 (t, J = 6.5 Hz, 2H), 1.09 (s, 9H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 135.5, 133.2, 129.7, 127.7, 63.9, 33.0, 26.7, 19.2. IR: ν 2921, 2857, 2358, 1428, 823, 700 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₈H₂₄OSiBr (M+H) 363.0780, found 363.0770.

Potassium {2-[(tert-Butyldiphenylsilyl)oxy]ethyl}trifluoroborate 1i: adapted from the borylation procedure reported by Marder and Liu:^11a a 20 mL vial was charged with CuI (55 mg, 10 mol %) and PPh₃ (99 mg, 13 mol %). Inside the glovebox was then added MeOLi (220 mg, 2 equiv) and B₂Pin₂ (1.1 g, 1.5 equiv). The vial was then sealed and removed from the glovebox. (2-Bromoethoxy)(tert-butyl)diphenylsilane (1.05 g, 2.89 mmol, 1 equiv) in dry DMF (15 mL) was added, and the resulting mixture stirred at rt overnight. The color of the soln rapidly changed from cloudy white to dark black. The reaction mixture was then diluted with EtOAc (20 mL), filtered through silica gel with copious washings (EtOAc, 20 mL) and concentrated. The crude mixture was then dissolved in MeOH (5 mL) and aqueous KHF₂ (4.5 M, 3 mL) was added dropwise at 0 °C. After 30 min stirring, the solvents were removed using a lyophilizer. The resulting white solid was dissolved in hot MeCN (10 mL) and sonicated, and the soln was filtered. The volume of the soln was reduced to ~2 mL, and the trifluoroborate was precipitated by addition of hexanes (10 mL) and Et₂O (5 mL), filtered and dried under vacuum to give 484 mg of the desired product as a white solid (43%). mp > 200 °C. ¹H NMR (DMSO-d⁶, 500 MHz):δ 7.62 (m, 4H), 7.40 (m, 6H), 3.66–3.62 (m, 2H), 0.95 (s, 9H), 0.51 (m, 2H). ¹³C NMR (DMSO-d⁶, 125.8 MHz):δ 135.4, 135.0, 129.7, 128.0, 65.3, 27.2, 19.1. ¹¹B NMR (DMSO-d⁶, 128.38 MHz):δ 5.16 (m). ¹⁹F NMR (DMSO-d⁶, 470.84 MHz):δ -135.8. IR: ν 2929, 1472, 1428, 1247, 1061, 1031, 940, 706 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₈H₂₃OSiF₃B (M – K)⁻ 351.1563, found 351.1564.

General Procedure for the Cross-Coupling of Alkoxyethyltrifluoroborates and Aryl or Heteroaryl Halides

In an oven-dried 8 mL microwave vial was introduced bis(di-tert-butyl(4-dimethylaminophenyl)-phosphine)dichloropalladium(II) (9 mg, 5 mol %), the alkoxyethyltrifluoroborate (0.275 mmol, 1.2 equiv) and Cs₂CO₃ (244 mg, 3 equiv). The vial was sealed with a cap lined with a disposable PTFE septum and evacuated under vacuum and purged with N₂ (x3). Degassed toluene (1 mL) and H₂O (0.25 mL) were added by syringe, followed by the desired electrophile (1 equiv). (When the aryl or heteroaryl halide was a solid, it was added after the base). The reaction mixture was then placed in an oil bath preheated at 100 °C and stirred for 24 h at this temperature. After cooling to rt, the vial was uncapped and diluted with H₂O (3 mL) and EtOAc (5 mL x 2). The combined organics were dried (MgSO₄) and filtered through Celite and concentrated in vacuo. Purification of the crude was performed by flash chromatography with hexanes/EtOAc: 100/0 to 80/20 with 1% Et₃N.

1-(2-(Benzyloxy)ethyl)-4-methoxybenzene 2a:²³ obtained as a colorless oil (49.5 mg, 82%). ¹H NMR (CDCl₃, 500 MHz):δ 7.37–7.30 (m, 5H), 7.18 (d, J = 8.5 Hz, 2H), 6.87 (dd, J = 7.0, 2.5 Hz, 2H), 4.56 (s, 2H), 3.82 (s, 3H), 3.69 (t, J = 7.0 Hz, 2H), 2.91 (t, J = 7.0 Hz, 2H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 158.0, 138.4, 131.0, 129.8, 128.3, 127.5, 127.4, 113.7, 72.9, 71.4, 55.2, 35.4. IR: ν 2931, 2855, 1512, 1246, 1100, 1036, 739 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₆H₁₈O₂Na (M+Na) 265.1204, found 265.1194.

1-(2-(Benzyloxy)ethyl)-2-methoxybenzene 2b: obtained as a colorless oil (56.0 mg, 92%). ¹H NMR (CDCl₃, 500 MHz):δ 7.37–7.35 (m, 4H), 7.32–7.30 (m, 1H), 7.24 (t, J = 7.0 Hz, 2H), 6.93 (td, J = 7.5, 1.0 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 4.58 (s, 2H), 3.83 (s, 3H), 3.73 (t, J = 7.0 Hz, 2H), 3.02 (t, J = 7.0 Hz, 2H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 157.6, 138.6, 130.6, 128.2, 127.5, 127.4, 127.3, 127.1, 120.3, 110.2, 72.7, 69.8, 55.2, 30.8. IR: ν 2360, 1494, 1243, 1099, 1028, 751 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₆H₁₈O₂Na (M+Na) 265.1204, found 265.1212.

1-(2-(Benzyloxy)ethyl)-3-methoxybenzene 2c: obtained as a yellow oil (56.4 mg, 93%). ¹H NMR (CDCl₃, 500 MHz):δ 7.40–7.30 (m, 5H), 7.26 (t, J = 7.0 Hz, 1H), 6.87 (d, J = 7.5 Hz, 1H), 6.83 (br s, 1H), 6.81 (dd, J = 8.5, 2.0 Hz, 1H), 4.57 (s, 2H), 3.82 (s, 3H), 3.74 (t, J = 7.0 Hz, 2H), 2.96 (t, J = 7.0 Hz, 2H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 159.6, 140.5, 138.4, 129.2, 128.3, 127.6, 127.5, 121.3, 114.6, 111.6, 72.9, 71.1, 55.1, 36.4. IR: ν 2855, 1602, 1488, 1259, 1100, 737, 696 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₆H₁₈O₂ (M+) 242.1307, found 242.1311.

4-(2-(Benzyloxy)ethyl)-N,N-dimethylaniline 2d: obtained as a yellow oil (32.4 mg, 51%). ¹H NMR (CDCl₃, 500 MHz):δ 7.37–7.34 (m, 4H), 7.31–7.30 (m, 1H), 7.14 (d, J = 8.5 Hz, 2H), 6.73 (d, J = 8.5 Hz, 2H), 4.57 (s, 2H), 3.69 (t, J = 7.0 Hz, 2H), 2.95 (s, 6H), 2.89 (t, J = 7.0 Hz, 2H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 149.3, 138.5, 129.5, 128.3, 127.6, 127.4, 126.8, 112.9, 72.9, 71.8, 40.8, 35.3. IR: ν 2852, 1615, 1522, 1345, 1099, 947, 810, 644 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₇H₂₂NO (M+H) 256.1701, found 256.1689.

2-(2-(Benzyloxy)ethyl)-1,3-dimethylbenzene 2e: obtained as a yellow oil (49.6 mg, 82%). ¹H NMR (CDCl₃, 500 MHz):δ 7.40–7.38 (m, 4H), 7.35–7.33 (m, 1H), 7.08–7.04 (m, 3H), 4.60 (s, 2H), 3.62 (t, J = 7.0 Hz, 2H), 3.08 (t, J = 7.0 Hz, 2H), 2.39 (s, 6H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 138.4, 136.7, 135.0, 128.3, 128.1, 127.5, 126.1, 72.9, 68.8, 30.2, 19.9. IR: ν 2855, 1453, 1361, 1100, 1028, 770, 644 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₇H₁₉O (M-H) 239.1436, found 239.1439.

1-(2-(Benzyloxy)ethyl)-2-methylbenzene 2f: obtained as a colorless oil (630.5 mg, 93%). ¹H NMR (CDCl₃, 500 MHz):δ 7.38–7.36 (m, 4H), 7.31–7.29 (m, 1H), 7.20–7.16 (m, 4H), 4.58 (s, 2H), 3.70 (t, J = 7.0 Hz, 2H), 2.99 (t, J = 7.0 Hz, 2H), 2.35 (s, 3H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 138.4, 136.8, 136.3, 130.1, 129.3, 128.3, 127.5, 127.4, 126.3, 125.9, 72.9, 70.2, 33.5, 19.3. IR: ν = 2857, 1494, 1454, 1361, 1099, 1028, 740 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₆H₁₈O (M+) 226.1358, found 226.1367.

1-(2-(Benzyloxy)ethyl)naphthalene 2g: obtained as a colorless oil (48.3 mg, 74%). ¹H NMR (CDCl₃, 500 MHz):δ 8.11 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 7.5 Hz, 1H), 7.79 (d, J = 7.5 Hz, 1H), 7.57–7.51 (m, 2H), 7.47–7.43 (m, 2H), 7.39–7.33 (m, 5H), 4.60 (s, 2H), 3.89 (t, J = 7.0 Hz, 2H), 3.48 (t, J = 7.0 Hz, 2H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 138.3, 134.8, 133.8, 132.1, 128.7, 128.3, 127.6, 127.5, 127.0, 126.8, 125.9, 125.5, 125.4, 123.7, 73.0, 70.6, 33.4. IR: ν 2856, 1454, 1361, 1100, 1027, 776, 608 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₉H₁₈ONa (M+Na) 285.1255, found 285.1250.

2-(2-(Benzyloxy)ethyl)naphthalene 2h: obtained as a yellow solid (58.5 mg, 89%). mp = 35–36 °C. ¹H NMR (CDCl₃, 500 MHz):δ 7.88 (d, J = 7.5 Hz, 1H), 7.85 (d, J = 8.5 Hz, 2H), 7.75 (br s, 1H), 7.54–7.49 (m, 2H), 7.45 (dd, J = 8.5, 1.2 Hz, 1H), 7.42–7.38 (m, 4H), 7.34–7.37 (m, 1H), 4.62 (s, 2H), 3.86 (t, J = 7.0 Hz, 2H), 3.18 (t, J = 7.0 Hz, 2H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 138.4, 136.6, 133.6, 132.2, 28.4, 127.8, 127.7, 127.6, 127.5, 127.4, 127.2, 125.9, 125.3, 73.0, 71.1, 36.5. IR: ν 2866, 1368, 1098, 1074, 821, 740 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₉H₁₈O (M+) 262.1358, found 262.1353.

1-(2-(Benzyloxy)ethyl)-2-(trifluoromethyl)benzene 2i: obtained as a colorless oil (53.6 mg, 76%). ¹H NMR (CDCl₃, 500 MHz):δ 7.65- 7.67 (m, 1H), 7.50–7.46 (m, 1H), 7.45–7.42 (m, 1H), 7.40–7.28 (m, 6H), 4.56 (s, 2H), 3.75 (t, J = 7.0 Hz, 2H), 3.17 (t, J = 7.0 Hz, 2H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 138.2, 137.4, 131.8, 131.5, 128.6 (q, J = 29.5 Hz), 128.3, 127.5, 127.4, 126.2, 125.8 (q, J = 5.7 Hz), 124.5 (d, J = 273.9 Hz), 72.8, 70.5, 32.9. ¹⁹F NMR (CDCl₃, 470.84 MHz):δ -59.6. IR: ν = 2980, 1313, 1114, 769, 741 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₆H₁₅OF₃ (M+) 280.1075, found 280.1071.

1-(2-(Benzyloxy)ethyl)-4-(trifluoromethyl)benzene 2j: obtained as a white solid (62.1 mg, 89%). mp = 44–46 °C. ¹H NMR (CDCl₃, 500 MHz):δ 7.58 (d, J = 8.0 Hz, 2H), 7.38–7.35 (m, 3H), 7.33–7.30 (m, 4H), 4.56 (s, 2H), 3.75 (t, J = 7.0 Hz, 2H), 3.01 (t, J = 7.0 Hz, 2H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 143.3, 138.1, 129.2, 128.5 (q, J = 32.0 Hz), 128.3, 127.6, 127.5, 125.1 (q, J = 3.9 Hz), 124.3 (d, J = 271.6 Hz), 73.0, 70.4, 36.1. ¹⁹F NMR (CDCl₃, 470.84 MHz):δ -62.3. IR: ν 2868, 2362, 1322, 1114, 1066, 738 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₆H₁₄OF₃ (M-H) 279.0997, found 279.0994.

1-(2-(Benzyloxy)ethyl)-4-fluorobenzene 2k: obtained as a yellow oil (44.3 mg, 77%). ¹H NMR (CDCl₃, 300 MHz):δ 7.37–7.31 (m, 5H), 7.24–7.20 (m, 2H), 7.19–6.98 (m, 2H), 4.56 (s, 2H), 3.71 (t, J = 7.0 Hz, 2H), 2.94 (t, J = 7.0 Hz, 2H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 161.4 (d, J = 243.8 Hz), 138.3, 134.6 (d, J = 3.0 Hz), 130.2 (d, J = 8.3 Hz), 128.3, 127.5, 127.4, 115.0 (d, J = 21.1 Hz), 72.9, 71.0, 35.5. ¹⁹F NMR (CDCl₃, 282.40 MHz):δ -117.3. IR: ν = 2861, 1509, 1221, 1098, 834, 825, 736 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₅H₁₅OF (M+) 230.1107, found 230.1100.

4-(2-(Benzyloxy)ethyl)benzonitrile 2l: obtained as a white solid [52.3 mg, 88% (from X = Cl)]. mp = 45–47 °C. ¹H NMR (CDCl₃, 500 MHz):δ 7.58 (d, J = 8.0 Hz, 2H), 7.36–7.33 (m, 4H), 7.31 (m, 1H), 7.30–7.27 (m, 2H), 4.52 (s, 2H), 3.72 (t, J = 7.0 Hz, 2H), 2.99 (t, J = 7.0 Hz, 2H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 144.9, 138.0, 132.0, 129.7, 128.3, 127.6, 127.5, 119.0, 110.0, 73.0, 69.9, 36.4. IR: ν 2866, 2224, 1608, 1364, 1096, 1077, 847, 746 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₆H₁₅NO (M+) 237.1154, found 237.1165.

4-(2-(Benzyloxy)ethyl)benzonitrile 2m: obtained as a yellow oil (39.7 mg, 67%). ¹H NMR (CDCl₃, 500 MHz):δ 7.63 (d, J = 7.5 Hz, 1H), 7.53 ( t, J = 8.0 Hz, 1H), 7.42 (d, J = 7.5 Hz, 1H), 7.35–7.31 (m, 3H), 7.30–7.27 (m, 3H), 4.55 (s, 2H), 3.79 (t, J = 7.0 Hz, 2H), 3.18 (t, J = 7.0 Hz, 2H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 143.0, 138.0, 132.7, 132.5, 130.3, 128.3, 127.5, 127.4, 126.8, 118.0, 112.7, 72.8, 69.5, 34.8. IR: ν 2861, 2224, 1452, 1361, 1099, 762, 738 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₆H₁₆NO (M+H) 238.1232, found 238.1229.

4-(2-(Benzyloxy)ethyl)benzaldehyde 2n: obtained as a yellow oil (44.7 mg, 74%). ¹H NMR (CDCl₃, 500 MHz):δ 10.00 (s, 1H), 7.82 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 7.0 Hz, 2H), 7.30–7.28 (m, 3H), 4.54 (s, 2H), 3.75 (t, J = 7.0 Hz, 2H), 3.02 (t, J = 7.0 Hz, 2H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 191.9, 146.6, 138.1, 134.7, 129.8, 129.5, 128.3, 127.6, 127.5, 73.0, 70.2, 36.5. IR: ν 2856, 1698, 1607, 1212, 1169, 1099, 741 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₆H₁₇O₂ (M+H) 241.1229, found 241.1222.

1-(4-(2-(Benzyloxy)ethyl)phenyl)ethanone 2o: obtained as a yellow oil (52.4 mg, 82%). ¹H NMR (CDCl₃, 500 MHz):δ 7.91 (d, J = 8.0 Hz, 2H), 7.35–7.33 (m, 4H), 7.33–7.29 (m, 3H), 4.54 (s, 2H), 3.73 (t, J = 7.0 Hz, 2H), 3.00 (t, J = 7.0 Hz, 2H), 2.60 (s, 3H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 197.7, 144.9, 138.1, 135.3, 129.1, 128.4, 128.3, 127.6, 127.5, 72.9, 70.4, 36.3, 26.5. IR: ν 2863, 2363, 1681, 1607, 1359, 1267, 1100, 956, 644 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₇H₁₉O₂ (M+H) 255.1385, found 255.1383.

Methyl 4-(2-(Benzyloxy)ethyl)benzoate 2p: obtained as a yellow solid (62.2 mg, 92%). mp = 27–29 °C. ¹H NMR (CDCl₃, 500 MHz):δ 7.98 (d, J = 8.0 Hz, 2H), 7.36–7.29 (m, 7H), 4.53 (s, 2H), 3.92 (s, 3H), 3.73 (t, J = 7.0 Hz, 2H), 2.99 (t, J = 7.0 Hz, 2H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 167.0, 144.6, 138.1, 129.6, 128.9, 128.3, 128.1, 127.6, 127.5, 72.9, 70.4, 51.9, 36.3. IR: ν 2862, 1719, 1610, 1278, 1105, 645 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₇H₁₉O₃ (M+H) 271.1334, found 271.1336.

1-(2-(Benzyloxy)ethyl)-4-nitrobenzene 2q: obtained as an orange solid (60.0 mg, 93%). mp = 45–46 °C. ¹H NMR (CDCl₃, 500 MHz):δ 8.15 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 7.35–7.33 (m, 2H), 7.31–7.27 (m, 3H), 4.53 (s, 2H), 3.75 (t, J = 7.0 Hz, 2H), 3.03 (t, J = 7.0 Hz, 2H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 147.2, 146.6, 137.9, 129.7, 128.3, 127.6, 127.5, 123.4, 73.0, 69.8, 36.1. IR: ν 2862, 1598, 1508, 1341, 1123, 856, 739 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₅H₁₆NO₃ (M+H) 258.1130, found 258.1138.

N-(4-(2-(Benzyloxy)ethyl)phenyl)acetamide 2r: obtained as a white solid (59.0 mg, 87%). mp = 102–104 °C. ¹H NMR (CDCl₃, 500 MHz):δ 7.42 (d, J = 8.5 Hz, 2H), 7.34–7.28 (m, 6H), 7.18 (d, J = 8.5 Hz, 2H), 4.53 (s, 2H), 3.68 (t, J = 7.0 Hz, 2H), 2.90 (t, J = 7.0 Hz, 2H), 2.16 (s, 3H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 168.2, 138.3, 136.0, 135.0, 129.3, 128.3, 127.5, 127.4, 119.9, 72.9, 71.1, 35.7, 24.4. IR: ν 3310, 1660, 1607, 1322, 1114, 834, 738 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₇H₂₀NO₂ (M+H) 270.1494, found 270.1487.

4-(2-(Benzyloxy)ethyl)benzenesulfonamide 2s: obtained as a white solid (25.0 mg, 34%). mp = 114–115 °C. ¹H NMR (CDCl₃, 500 MHz):δ 7.85 (d, J = 7.5 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.36–7.33 (m, 2H), 7.30–7.27 (m, 3H), 4.89 (br s, 2H) 4.52 (s, 2H), 3.72 (t, J = 7.0 Hz, 2H), 3.00 (t, J = 7.0 Hz, 2H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 144.8, 139.7, 137.9, 129.6, 128.3, 127.6, 127.5, 126.4, 73.0, 70.1, 36.1. IR: ν 3335, 3263, 2868, 2360, 2342, 1307, 1160, 903, 686 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₅H₁₆NO₃S (M-H) 290.0851, found 290.0864.

3-(2-(Benzyloxy)ethyl)pyridine 3a: obtained as a yellow oil (28.8 mg, 54%). ¹H NMR (CDCl₃, 500 MHz):δ 8.51 (s, 1H), 7.48 (d, J = 5.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.40–7.33 (m, 2H), 7.32–7.28 (m, 3H), 7.21 (dd, J = 5.0, 7.5 Hz, 1H), 4.52 (s, 2H), 3.70 (t, J = 7.0 Hz, 2H), 2.92 (t, J = 7.0 Hz, 2H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 150.2, 147.6, 138.0, 136.3, 134.5, 128.3, 127.6, 127.5, 123.1, 73.0, 70.3, 33.4. IR: ν 2858, 2362, 1361, 1100, 1028, 699 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₄H₁₆NO (M+H) 214.1232, found 214.1223.

5-(2-(Benzyloxy)ethyl)-2-methoxypyridine 3b: obtained as a yellow oil (42.6 mg, 70%). ¹H NMR (CDCl₃, 500 MHz):δ 8.18 (d, J = 2.5 Hz, 1H), 8.12 (s, 1H), 7.35–7.27 (m, 5H), 7.10 (s, 1H), 4.52 (s, 2H), 3.83 (s, 3H), 3.71 (t, J = 7.0 Hz, 2H), 2.91 (t, J = 7.0 Hz, 2H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 155.4, 142.5, 138.0, 135.3, 128.3, 127.6, 127.5, 127.4, 121.1, 73.0, 70.3, 55.4, 33.3. IR: ν 2852, 2362, 1588, 1283, 1100, 868, 699 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₅H₁₈NO₂ (M+H) 244.1338, found 244.1328.

2-(2-(Benzyloxy)ethyl)pyridine 3c: obtained as a colorless oil [16.5 mg, 31% (from X = Cl)]. ¹H NMR (CDCl₃, 500 MHz):δ 8.54 (d, J = 5.0 Hz, 1H), 7.60 (t, J= 7.5 Hz, 1H), 7.34–7.27 (m, 5H), 7.23 (m, 1H), 7.13 (t, J = 7.5 Hz, 1H), 4.54 (s, 2H), 3.88 (t, J = 7.0 Hz, 2H), 3.12 (t, J = 7.0 Hz, 2H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 159.2, 149.2, 138.3, 136.1, 128.2, 127.5, 127.4, 123.5, 121.2, 72.9, 69.5, 38.6. IR: ν 2851, 2362, 1592, 1093, 749, 698 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₄H₁₆NO (M+H) 214.1232, found 214.1225.

5-(2-(Benzyloxy)ethyl)quinoline 3d: obtained as a yellow oil (55.0 mg, 83%). ¹H NMR (CDCl₃, 500 MHz):δ 8.91 (d, J = 1.5 Hz, 1H), 8.38 (d, J = 8.5 Hz, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.64 (dd, J = 8.5, 7.5 Hz, 1H), 7.44 (d, J= 7.0 Hz, 1H), 7.39 (dd, J = 7.5, 4.5 Hz, 1H), 7.33–7.26 (m, 5H), 4.53 (s, 2H), 3.81 (t, J = 7.0 Hz, 2H), 3.39 (t, J = 7.0 Hz, 2H). ¹³C NMR (CDCl₃, 125.8 MHz):δ = 149.9, 148.6, 138.1, 135.5, 132.2, 129.0, 128.3, 127.6, 127.5, 127.2, 127.1, 120.7, 73.0, 70.4, 32.6. IR: ν = 2855, 2362, 1500, 1362, 1100, 802 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₈H₁₈NO (M+H) 264.1388, found 264.1380.

4-(2-(Benzyloxy)ethyl)isoquinoline 3e: obtained as a yellow oil (50.5 mg, 77%). ¹H NMR (CDCl₃, 500 MHz):δ 9.16 (s, 1H), 8.44 (s, 1H), 8.0 (d, J = 8.5 Hz, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.71 (m, 1H), 7.61 (m, 1H), 7.34–7.27 (m, 5H), 4.55 (s, 2H), 3.84 (t, J = 7.0 Hz, 2H), 3.36 (t, J = 7.0 Hz, 2H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 151.5, 143.3, 138.1, 134.8, 130.2, 128.4, 128.3, 128.2, 128.1, 127.6, 127.5, 126.8, 122.8, 73.0, 70.0, 30.5. IR: ν 2918, 2362, 1622, 1100, 896, 748 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₈H₁₈NO (M+H) 264.1388, found 264.1380. tert-Butyl

5-(2-(Benzyloxy)ethyl)-1H-indole-1-carboxylate 3f: obtained as a yellow solid (78.4 mg, 89%). mp = 28–30 °C. ¹H NMR (CDCl₃, 500 MHz):δ 8.08 (m, 1H), 7.60 (d, J = 3.5 Hz, 1H), 7.44 (d, J = 1.0 Hz, 1H), 7.38–7.34 (m, 4H), 7.32–7.30 (m, 1H), 7.22 (dd, J = 8.5, 1.5 Hz, 1H), 6.54 (d, J = 3.5 Hz, 1H), 4.57 (s, 2H), 3.76 (t, J = 7.0 Hz, 2H), 3.06 (t, J = 7.0 Hz, 2H), 1.70 (s, 9H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 149.7, 138.4, 133.8, 133.2, 130.7, 128.3, 127.6, 127.4, 126.0, 125.3, 120.9, 114.9, 107.1, 83.4, 72.9, 71.7, 36.2, 28.1. IR: ν 2851, 1729, 1470, 1372, 1352, 1163, 1091, 1026, 648 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₂₂H₂₅NO₃Na (M+Na) 374.1732, found 374.1727.

5-(2-(Benzyloxy)ethyl)-1H-indole 3g: obtained as a yellow oil (34.4 mg, 55%). ¹H NMR (CDCl₃, 500 MHz):δ 8.14 (br s, 1H), 7.53 (s, 1H), 7.38 (m, 4H), 7.32 (m, 2H), 7.17 (t, J = 2.5 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 6.53 (m, 1H), 4.60 (s, 2H), 3.79 (t, J = 7.0 Hz, 2H), 3.09 (t, J = 7.0 Hz, 2H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 138.5, 134.6, 130.0, 128.3, 128.1, 127.6, 127.4, 124.3, 123.3, 120.5, 110.8, 102.2, 72.9, 72.2, 36.4. IR: ν 3414, 1477, 1332, 1093, 726, 648 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₇H₁₈NO (M+H) 252.1388, found 252.1379.

5-(2-(Benzyloxy)ethyl)pyrimidine 3h: obtained as an orange oil (36.8 mg, 69%). ¹H NMR (CDCl₃, 500 MHz):δ 9.09 (s, 1H), 8.64 (s, 2H), 7.34–7.29 (m, 2H), 7.29–7.23 (m, 3H), 4.51 (s, 2H), 3.70 (t, J = 7.0 Hz, 2H), 2.89 (t, J = 7.0 Hz, 2H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 157.1, 157.0, 137.7, 132.6, 128.4, 127.7, 127.5, 73.1, 69.3, 30.9. IR: ν 2853, 2359, 1560, 1409, 1097, 728 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₃H₁₄N₂O (M+) 214.1106, found 214.1099.

3-(2-(Benzyloxy)ethyl)thiophene 3i:²⁴ obtained as a colorless oil (48.1 mg, 88%). ¹H NMR (CDCl₃, 500 MHz):δ 7.38–7.33 (m, 4H), 7.32 (m, 1H), 7.28 (m, 1H), 7.06 (m, 1H), 7.03 (m, 1H), 4.58 (s, 2H), 3.74 (t, J = 7.0 Hz, 2H), 3.00 (t, J = 7.0 Hz, 2H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 139.2, 138.3, 128.5, 128.3, 127.6, 127.5, 125.1, 121.1, 72.9, 70.4, 30.7. IR: ν 2360, 2341, 1453, 1099, 737, 648 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₃H₁₄OS (M+) 218.0765, found 218.0766.

1-Methoxy-4-(2-methoxyethyl)benzene 4a:²⁵ obtained as a colorless oil (26.3 mg, 63%). ¹H NMR (CDCl₃, 500 MHz):δ 7.15 (d, J = 8.5 Hz, 2H), 6.85 (dd, J = 7.0, 2.0 Hz, 2H), 3.80 (s, 3H), 3.58 (t, J = 7.0 Hz, 2H), 3.37 (s, 3H), 2.84 (t, J = 7.0 Hz, 2H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 158.0, 130.9, 129.7, 127.3, 114.0, 113.7, 73.8, 58.5, 55.1, 35.2. IR: ν 2833, 1513, 1246, 1114, 1034, 833 cm⁻¹. HRMS (ESI- TOF) m/z calcd. For C₁₀H₁₅O₂ (M+H) 167.1072, found 167.1069.

1-(2-Ethoxyethyl)-4-methoxybenzene 4b: obtained as a colorless oil (32.5 mg, 72%). ¹H NMR (CDCl₃, 500 MHz):δ 7.16 (d, J = 8.5 Hz, 2H), 6.85 (dd, J = 7.0, 2.0 Hz, 2H), 3.80 (s, 3H), 3.61 (t, J = 7.5 Hz, 2H), 3.52 (q, J = 7.0 Hz, 2H), 2.85 (t, J = 7.5 Hz, 2H), 1.22 (t, J = 7.0 Hz, 3H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 158.0, 131.0, 129.7, 127.3, 113.7, 71.8, 66.1, 55.1, 35.4, 15.1. IR: ν 2854, 1612, 1513, 1245, 1109, 1037, 830 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₁H₁₆O₂ (M+) 180.1150, found 180.1152.

2-(4-Methoxyphenethoxy)tetrahydro-2H-pyran 4c:²⁶ obtained as a colorless oil (45.5 mg, 77%). ¹H NMR (CDCl₃, 500 MHz):δ 7.17 (d, J = 8.5 Hz, 2H), 6.84 (dd, J = 7.0, 2.0 Hz, 2H), 4.60 (t, J = 3.5 Hz, 1H), 3.95–3.90 (m, 1H), 3.85–3.77 (m, 1H), 3.79 (s, 3H), 3.62–3.57 (m, 1H), 3.48–3.46 (m, 1H), 2.87 (t, J = 7.0 Hz, 2H), 1.89–1.79 (m, 1H), 1.74–1.68 (m, 1H), 1.63–1.47 (m, 4H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 158.0, 131.1, 129.8, 113.6, 98.6, 68.4, 62.1, 55.1, 35.4, 30.6, 25.4, 19.4. IR: ν 2939, 1513, 1246, 1120, 1030, 824 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₄H₂₀O₃ (M+) 236.1412, found 236.1406.

1-Methoxy-4-(2-phenoxyethyl)benzene 4d:²⁷ obtained as a colorless oil (18.0 mg, 31%). ¹H NMR (CDCl₃, 500 MHz):δ 7.31–7.28 (m, 2H), 7.23 (d, J = 8.5 Hz, 2H), 6.96 (t, J = 7.5 Hz, 1H), 6.93 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 4.16 (t, J = 7.0 Hz, 2H), 3.82 (s, 3H), 3.06 (t, J = 7.0 Hz, 2H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 158.7, 158.2, 130.2, 129.9, 129.3, 120.6, 114.5, 113.8, 68.7, 55.2, 34.8. IR: ν 2360, 1513, 1243, 1176, 1034, 825, 754 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₅H₁₆O₂ (M+) 228.1150, found 228.1144.

2-(4-Methoxybenzyl)tetrahydro-2H-pyran 4e: obtained as a colorless oil (36.3 mg, 70%). ¹H NMR (CDCl₃, 500 MHz):δ 7.14 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 4.00–3.98 (m, 1H), 3.80 (s, 3H), 3.46–3.39 (m, 2H), 2.83 (dd, J = 14.0, 7.0 Hz, 1H), 2.60 (dd, J = 14.0, 7.0 Hz, 1H), 1.82 (dd, J = 13.0, 2.0 Hz, 1H), 1.63–1.55 (m, 2H), 1.52–1.47 (m, 1H), 1.46–1.41 (m, 1H), 1.32–1.24 (m, 1H). ¹³C NMR (CDCl₃, 125.8 MHz):δ 157.9, 130.8, 130.2, 113.5, 78.9, 68.5, 55.1, 42.2, 31.3, 26.0, 23.4. IR: ν 2934, 1512, 1245, 1090, 1039, 648 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₃H₁₉O₂ (M+H) 207.1385, found 207.1385.

2-((4-Methoxyphenethoxy)methyl)-2,3-dihydrobenzo[b][1,4]dioxine 4f: obtained as a white solid (31.2 mg, 49%). mp = 68–71 °C. ¹H NMR (CDCl₃, 500 MHz):δ 7.20 (d, J = 8.0 Hz, 2H), 6.91–6.84 (m, 4H), 6.89 (d, J = 8.0 Hz, 2H), 4.33 (qd, J = 7.2, 2.0 Hz, 1H), 4.19 (dd, J = 11.2, 2.2 Hz, 1H), 3.91 (dd, J = 11.2, 7.0 Hz, 1H), 3.83 (s, 3H), 3.07 (dd, J = 14.0, 7.0 Hz, 1H), 2.85 (dd, J = 14.0, 7.0 Hz, 1H). ¹³C NMR (CDCl₃, 125.8 MHz):δ = 158.4, 143.2, 143.1, 130.3, 128.3, 121.4, 121.1, 117.3, 116.9, 114.0, 73.8, 66.9, 55.2, 36.6. IR: ν 1610, 1592, 1514, 1493, 1268, 1243, 1036, 754 cm⁻¹. HRMS (ESI-TOF) m/z calcd. For C₁₆H₁₆O₃ (M+) 256.1099, found 256.1104.

Table 2.

Suzuki Cross-Coupling of Benzyloxyethyltrifluoroborate 1c and Various Heteroaryl Bromides.^a

entry	electrophile	product	isolated yield (%)b
1		3a	54
2		3b	70
3		3c	10 (C1)
4		3d	83
5		3e	77
6		3f	89
7		3g	55
8		3h	69
9		3i	88c

^aGeneral conditions: heteroaryl bromide/chloride (0.25 mmol), trifluoroborate (0.275 mmol), Cs₂CO₃ (0.75 mmol) in toluene (1 mL)/H₂O (0.25 mL) at 100 °C for 24 h.

^bIsolated yield after purification by flash chromatography on silica gel.

^cContaminated by up to 8% impurity.