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. Author manuscript; available in PMC: 2021 Mar 6.
Published in final edited form as: J Org Chem. 2020 Feb 18;85(5):3717–3727. doi: 10.1021/acs.joc.9b03373

Scalable and Phosphine-Free Conversion of Alcohols to Carbon–Heteroatom Bonds through the Blue Light-Promoted Iodination Reaction

Bin Liu 1, W Zachary Elder 2, Garret M Miyake 3
PMCID: PMC7170005  NIHMSID: NIHMS1580125  PMID: 32019308

Abstract

One of the fundamental and highly valuable transformations in organic chemistry is the nucleophilic substitution of alcohols. Traditionally, these reactions require strategies that employ stoichiometric hazardous reagents and are associated with difficulty in purification of the by-products. To overcome these challenges, here, we report a simple route toward the diverse conversion of alcohols via an SN2 pathway, in which blue light-promoted iodination is used to form alkyl iodide intermediates from simple unreactive alcohols. The scope of the process tolerates a range of nucleophiles to construct C–N, C–O, C–S, and C–C bonds. Furthermore, we also demonstrate that this method can be used for the preparation and late-stage functionalization of pharmaceuticals, as highlighted by the syntheses of thiocarlide, butoxycaine, and pramoxine.

Graphical Abstract

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INTRODUCTION

Alcohols represent one of the most abundant organic molecules among drugs, bioactive natural products, and synthetic intermediates.1 Therefore, various strategies have been developed for the conversion of alcohols into a wide range of different functional groups, such as alkenes, halides, aldehydes, ketones, carboxylic acids, and esters.2 Among them, nucleophilic substitution reactions of alcohols through a redox combination of a trialkyl or triarylphosphine and a dialkyl azodicarboxylate (Mitsunobu reaction) (Figure 1a)3 or combination of triphenylphosphine and an electrophilic halogen source such as tetrachloromethane (CCl4), tetrabromomethane (CBr4), or I2 (under Appel conditions)4 have been extensively investigated and applied to the syntheses of drugs and natural products. However, both of these methodologies employ triphenylphosphine as a reductant, which is converted to triphenylphosphine oxide and is difficult to remove. Moreover, for the Mitsunobu reaction, the high-energy and relatively expensive reagent, azodicarboxylate, is required. The arduous separation of stoichiometric waste by-product, poor atom economy,5 and the use of a high-energy reagent limit the use of the reaction on a scale in process chemistry.6 Although phosphine oxide-catalyzed Mitsunobu reactions have been developed recently,7 the scope of pronucleophiles is limited (Figure 1b). Consequently, the development of more general and applicable approaches for the transformation of alcohols has involved continuous efforts in both academe and industry.

Figure 1.

Figure 1.

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Development of nucleophilic substitution reactions of alcohols. (a) Mitsunobu reaction. (b) Redox-neutral organocatalytic Mitsunobu reaction. (c) Photoredox-catalyzed conversion of alcohols to halides. (d) Visible-light-driven iodination of alcohols. (e) This work: diverse conversion of alcohols through blue light-promoted iodination reaction. Nu: nucleophile.

Alkyl halides8 and alkyl sulfonates9 are representative substrates for SN2 reactions that can be used in a variety of carbon-carbon and carbon-heteroatom bond-forming reactions.10 However, preparation of these reagents is traditionally difficult, and stoichiometric waste needs to be separated to facilitate subsequent nucleophilic substitution reactions. To enable diverse conversion of alcohols, we questioned whether it would be possible to use in situ-generated alkyl halides from alcohols as an intermediate without purification and subsequently employ bimolecular nucleophilic substitution (SN2) reactions to prepare derivatives or analogues in a one-pot reaction.11

To generate the targeted alkyl halide in situ, we investigated established procedures for the visible-light-mediated conversion of alcohols to alkyl halides using CBr4 or CHI3 (Figure 1c,d), en route to the targeted construction of carbon-heteroatom bonds in a one-pot reaction because of the demonstrated good functional group tolerance for the iodination reaction that proceeded under mild conditions.12 Herein, we report the transformation of alcohols through blue light-promoted iodination in a two-step, one-pot reaction. In the presence of dimethylformamide (DMF) and under blue light-emitting diode (LED) irradiation, alcohols and iodoform react to yield an alkyl iodide. Subsequent addition of the nucleophile and base to the reaction mixture containing the alkyl iodide generated the corresponding substitution products with excellent yields (Figure 1e). This process represents the direct and diverse conversion of alcohols with a wide range of nucleophiles via an alkyl iodide intermediate, avoiding the handling of phosphine, use of diethyl azodicarboxylate (DEAD), and the isolation of alkyl halides or alkyl tosylates. We further demonstrate that this mild nucleophile substitution procedure can serve as a powerful and general method in the preparation of medicinally relevant molecules and for the late-stage functionalization of bioactive compounds.

RESULTS AND DISCUSSION

Our initial discovery arose from our continuing interest in visible-light-driven and transition-metal-free chemistry.13 When CBr4 was utilized as the bromide source and 3,7-di(4-biphenyl) 1-naphthalene-10-phenoxazine as the catalyst, the brominated product of 6-hydroxyhexyl benzoate was produced in 39% yield. Encouragingly, the iodination product was detected in high yield with blue LED irradiation of a solution containing 6-hydroxyhexyl benzoate, iodoform, and the phenoxazine organic photoredox catalyst in DMF. Furthermore, the desired product could also be isolated in high yield (90%) in the absence of the organic photoredox catalyst after 20 h of blue LED irradiation at room temperature,14 similar to published reports.12b,c The iodination product was also obtained in high yield by switching the solvent to N,N′-dimethylacetamide (DMAc) or N-methyl-2-pyrrolidone (NMP). Without isolation of iodinated products, we investigated potential for a one-pot nucleophilic substitution using 4-bromobenzoic acid as the pronucleophile. Encouragingly, the ester product (49) was isolated in 89% yield after heating the reaction solution after addition of 4-bromobenzoic acid and K2CO3.

To investigate the generality and robustness of the reaction conditions, we then explored the scope of suitable alcohols. A variety of alcohols bearing different functional groups were all competent substrates (Figure 2, 1–11). Secondary alcohol cyclopentanol provided the ester product in 30% yield (1). Unprotected indole ethanol was tolerated and afforded the desired product in 23% yield (4). Substrates containing ether functional groups afforded the corresponding products in excellent yields (5, 6, and 8). Primary alcohols bearing alkene functionalities were esterified in good yields (3 and 7) under mild reaction conditions. A terminal alkyne containing alcohol was transformed to the corresponding product in 85% yield (9). It is noteworthy that a substrate containing a phosphine-sensitive alkyl azide (10) was compatible with the robust reaction conditions.

Figure 2.

Figure 2.

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Scope of alcohols. Reaction conditions: alcohol (0.5 mmol), iodoform (1.0 mmol), 4-bromobenzoic acid (1.0 mmol), K2CO3 (4.0 mmol), and DMF (3.0 mL) with isolated yields provided.

We then sought to extend the reaction system to develop other synthetically useful carbon-heteroatom bond-forming processes. Using thiols as pronucleophiles allowed access to a range of thioether derivatives (Figure 3, 12–24). As shown in Figure 3, diverse thiophenols were found to be suitable pronucleophiles, including those with nitrogen-containing heterocycles (13–15 and 17–21). These common motifs are ubiquitous in pharmaceutical molecules. Alkyl thiols were also amenable, as demonstrated by the formation of thioether products in high yields (22 and 23). Moreover, thiobenzoic acid could also be converted to the corresponding thioester in 78% yield (24). We next investigated the use of nitrogen nucleophiles (Figure 3). Primary and secondary amines were successfully synthesized and provided the corresponding products in good yields (25 and 27–30). In addition to amines, phthalimide can also participate in the nucleophilic substitution reaction under this system (26). Azido and cyano groups were compatible with the reaction, affording the desired nucleophile substitution product in good yields (31 and32).

Figure 3.

Figure 3.

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C-S and C-N bond formations. Reaction conditions: 6-hydroxyhexyl benzoate (0.5 mmol), iodoform (1.0 mmol), pronucleophile (1.0 mmol), K2CO3 (4.0 mmol), and DMF (3.0 mL) with isolated yields provided.

To investigate the compatibility of this reaction system more thoroughly, the potential of using phenols and carboxylic acids was also explored (Figure 4). Heterocycles, including pyridine (35, 36, 40, and 46), quinoline (39), coumarin (37), indole (44 and 51), furan (48), and benzo[b]thiophene (50), are tolerated under the reaction conditions. When indomethacin was subjected to the standard reaction conditions, the deprotection product was also isolated in 38% yield. Other functionalities, including bromide (33 and 49), nitro (34), alkene (42, 43, and 47), and protected amine (52) groups, also participate well in the reaction. Interestingly, biotin (41) is also tolerated and generated the desired product in 84% yield. Furthermore, we successfully introduced diphenylphosphinic acid (53) to form the phosphinate product in 60% yield.

Figure 4.

Figure 4.

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C-O bond formation. Reaction conditions: 6-hydroxyhexyl benzoate (0.5 mmol), iodoform (1.0 mmol), pronucleophile (1.0 mmol), K2CO3 (4.0 mmol), and DMF (3.0 mL) with isolated yields provided.

To demonstrate our system’s potential utility, this strategy was applied to the late-stage diversification of ketoprofen. Under the standard reaction conditions, a variety of ketoprofen derivatives were efficiently prepared (54–57). Finally, we applied our strategy to the syntheses of thiocarlide,15 butoxycaine16 and pramoxine (Figure 5).17 Our one-pot SN2 reactions provide a convenient and atom-economical procedure to make aryl ethers in good yields (58–60), without handling triphenylphosphine or isolating the alkyl halides and alkyl sulfonates. The key structure of thiocarlide was synthesized by conversion of isoamyl alcohol to isoamyl iodide, which was reacted with acetaminophen in situ to produce the product 58 in 94% yield. This strategy afforded the product in higher yield compared with the recently reported phosphine oxide-catalyzed Mitsunobu reaction.7b Aryl ether product 59 was produced in 96% yield, avoiding the use of a palladium-catalyzed C-O cross-coupling reaction.16 In particular, we scaled up the production of 59 to 50 mmol, although the yield was reduced to 50%, most likely due to the high concentration of the solution or poorer irradiation of the larger reaction mixture.

Figure 5.

Figure 5.

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(a) Late-stage diversification of bioactive molecule. (b) Active pharmaceutical ingredient synthesis.

CONCLUSIONS

In sum, we have successfully developed a convenient and efficient approach for the diverse functionalization of alcohols through the direct iodination of alcohols with iodoform. As the traditional conversion of alcohols requires the isolation of alkyl halides or alkyl tosylates, this one-pot approach is expected to modernize this transformation by providing more direct syntheses and access to new products. A simple procedure for both the iodination and nucleophilic substitution reactions (SN2) in one-pot renders this protocol highly practical. This transformation has been applied to the late-stage functionalization of pharmaceutical reagents and the syntheses of thiocarlide, butoxycaine, and pramoxine. Further, the reaction was effectively scaled to employ 50 mmol of starting material. Considering the operational simplicity, broad functional group compatibility, and scalability of this reaction, we anticipate that this transformation will have both academic and industrial values.

EXPERIMENTAL SECTION

General Information.

Dimethylformamide (DMF), dimethylacetamide (DMAc), and N-methyl-2-pyrrolidone (NMP) were purchased from Sigma-Aldrich and sparged with nitrogen for 15 min at room temperature and stored under a nitrogen atmosphere. Hexane-1,6-diol was purchased from TCI America. CHI3 was purchased from Sigma-Aldrich. Thiols, phenols, carboxylic acids, and amines were purchased from Sigma-Aldrich, TCI, and Alfa Aesar. Organic solutions were concentrated under reduced pressure on a Büchi rotary evaporator using a water bath. The visible light source was a 16 in. strip of double-density blue LEDs, purchased from Creative Lighting Solutions (item no. CL-FRS5050WPDD-5M-12VBL), and wrapped inside a 400 mL beaker (Figure S1). The distance from the light source to the irradiation vessel is about 4 cm, and no filters are used.

The 1H and 13C nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz for 1H or at 101 MHz for 13C, respectively. Deuterated solvents were purchased from Cambridge Isotope Laboratories (Andover, MA) and used as-received. All 1H NMR experiments are reported in δ units, parts per million (ppm), and were measured relative to the signals for residual chloroform (7.26 ppm) in the deuterated solvent. Data for 1H NMR are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = quintet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, etc., br = broad), coupling constant (Hz), and integration. All 13C NMR spectra are reported in ppm relative to CDCl3 (77.0 ppm). Trimethoxybenzene was used as an internal standard for NMR yields from proton analysis for the 6-iodohexyl benzoate formation.

Flash column chromatography was performed by using a 100–150 times weight excess of flash silica gel 40–63 μm from Aldrich. Fractions were analyzed by thin-layer chromatography (TLC) using TLC silica gel F254 250 μm precoated plates from Merck, and permanganate stain was used for UV-inactive compounds. High-resolution mass spectra (HRMS) were obtained via direct analysis in real time mass spectrometry (DART-MS) on an Agilent 6210 TOF interfaced to the DART 100 source and Agilent 6224 time-of-flight (TOF) liquid chromatography-mass spectrometry) (LC-MS) provided by Colorado State University Central Instrument Facility.

General Procedure for Conversion of Alcohols.

A 50 mL storage flask was charged with a stir bar, flame dried under vacuum, and back filled with nitrogen three times. The flask was then charged with 6-hydroxyhexyl benzoate (111.1 mg, 0.5 mmol, 1.0 equiv), iodoform (397.7 mg, 1.0 mmol, 2.0 equiv), and 3.0 mL of DMAc. The reaction mixture was evacuated and purged with inert gas (N2) three times. The reaction mixture was then placed into an LED-lined beaker and stirred under compressed air cooling (room temperature). After the time specified in the reaction schemes, K2CO3 (552.8 mg, 4.0 mmol, 8.0 equiv) and pronucleophile (1.0 mmol, 2.0 equiv) were added into the reaction mixture and stirred at 100 °C using an oil bath for 20 h. The reaction mixture was washed with water and extracted with EtOAc. Purification of the crude product by flash chromatography on silica gel using the indicated solvent system afforded the desired product.

Synthesis of Drugs.

N-(4-(Isopentyloxy)phenyl)acetamide.

A 50 mL storage flask was charged with a stir bar, flame dried under vacuum, and back filled with nitrogen three times. The flask was then charged with 3-methylbutan-1-ol (88.2 mg, 1.0 mmol, 1.0 equiv), iodoform (795.5 mg, 2.0 mmol, 2.0 equiv), and 3.0 mL of DMAc. The reaction mixture was evacuated and purged with inert gas (N2) three times. The reaction mixture was then placed into an LED-lined beaker and stirred under compressed air cooling (room temperature). After the time specified in the reaction schemes, K2CO3 (552.8 mg, 4.0 mmol, 4.0 equiv) and pronucleophile (302.3 mg, 1.0 mmol, 2.0 equiv) were added into the reaction mixture and stirred at 100 °C for 20 h. The reaction mixture was washed with water and extracted with EtOAc. Purification by flash chromatography (1:1 EtOAc/hexanes) provided the title compound (310 mg) in 94% yield.

4-Butoxyphenol.

A 50 mL storage flask was charged with a stir bar, flame dried under vacuum, and back filled with nitrogen three times. The flask was then charged with butan-1-ol (74.1 mg, 1.0 mmol, 1.0 equiv), iodoform (795.5 mg, 2.0 mmol, 2.0 equiv), and 3.0 mL of DMAc. The reaction mixture was evacuated and purged with inert gas (N2) three times. The reaction mixture was then placed into an LED-lined beaker and stirred under compressed air cooling (room temperature). After the time specified in the reaction schemes, K2CO3 (552.8 mg, 4.0 mmol, 4.0 equiv) and pronucleophile (304.2 mg, 1.0 mmol, 2.0 equiv) were added into the reaction mixture and stirred at 100 °C for 20 h. The reaction mixture was washed with water and extracted with EtOAc. Purification by flash chromatography (1:4 EtOAc/hexanes) provided the title compound (101 mg) in 60% yield.

Methyl 4-Butoxybenzoate.

A 50 mL storage flask was charged with a stir bar, flame dried under vacuum, and back filled with nitrogen three times. The flask was then charged with butan-1-ol (74.1 mg, 1.0 mmol, 1.0 equiv), iodoform (795.5 mg, 2.0 mmol, 2.0 equiv), and 3.0 mL of DMAc. The reaction mixture was evacuated and purged with inert gas (N2) three times. The reaction mixture was then placed into an LED-lined beaker and stirred under compressed air cooling (room temperature). After the time specified in the reaction schemes, K2CO3 (552.8 mg, 4.0 mmol, 4.0 equiv) and pronucleophile (304.3 mg, 1.0 mmol, 2.0 equiv) were added into the reaction mixture and stirred at 100 °C for 20 h. The reaction mixture was washed with water and extracted with EtOAc. Purification by flash chromatography (1:9 EtOAc/hexanes) provided the title compound (200 mg) in 96% yield.

Multigram Scale Experiment.

A 250 mL storage flask was charged with a stir bar, flame dried under vacuum, and back filled with nitrogen three times. The flask was then charged with butan-1-ol (3.7 g, 50.0 mmol, 1.0 equiv), iodoform (39.3 g, 100.0 mmol, 2.0 equiv), and 100.0 mL of DMAc. The reaction mixture was evacuated and purged with inert gas (N2) three times. The reaction mixture was then placed into an LED-lined beaker and stirred under compressed air cooling (room temperature). After the time specified in the reaction schemes, K2CO3 (27.6 g, 200.0 mmol, 4.0 equiv) and pronucleophile (15.2 g, 100.0 mmol, 2.0 equiv) were added into the reaction mixture and stirred at 100 °C for 20 h. The reaction mixture was washed with water and extracted with EtOAc. Purification by flash chromatography (1:9 EtOAc/hexanes) provided the title compound (5.27 g) in 50% yield.

Cyclopentyl 4-Bromobenzoate (1).

41 mg; 30% yield. Physical state: colorless oil. Rf = 0.5 (silica gel, 1:10 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 7.94–7.79 (m, 2H), 7.62–7.51 (m, 2H), 5.39 (m, 1H), 2.03–1.90 (m, 2H), 1.90–1.75 (m, 4H), 1.74–1.60 (m, 2H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 165.6, 131.6, 131.0, 129.8, 127.7, 78.0, 32.7, 23.8. HRMS (DART) m/z: [M + H]+ calcd for C12H14BrO2, 269.0172; found, 269.0168.

2-(Pyridin-2-yl)ethyl 4-Bromobenzoate (2).

59 mg; 38% yield. Physical state: colorless oil. Rf = 0.5 (silica gel, 1:3 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.56 (ddd, J = 4.9, 1.9, 0.9 Hz, 1H), 7.84–7.81 (m, 2H), 7.61 (td, J = 7.6, 1.8 Hz, 1H), 7.56–7.52 (m, 2H), 7.22 (dt, J = 7.8, 1.1 Hz, 1H), 7.15 (m, 1H), 4.70 (t, J = 6.7 Hz, 2H), 3.24 (t, J = 6.7 Hz, 2H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 165.7, 157.9, 149.6, 136.4, 131.6, 131.1, 129.1, 128.0, 123.4, 121.7, 64.4, 37.4. HRMS (DART) m/z: [M + H]+ calcd for C14H13BrNO2, 306.0124; found, 306.0152.

4-((3aR,7aS)-1,3-Dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindol-2-yl)benzyl 4-Bromobenzoate (3).

150 mg; 66% yield. Physical state: white solid. Rf = 0.5 (silica gel, 1:1 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 7.93–7.90 (m, 2H), 7.55 (m, 4H), 7.40–7.18 (m, 2H), 6.34 (s, 2H), 5.35 (s, 2H), 3.40 (s, 2H), 2.86 (s, 2H), 1.63 (d, J = 10.0 Hz, 1H), 1.47 (d, J = 10.0 Hz, 1H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 176.9, 165.5, 137.9, 136.2, 131.8, 131.7, 131.2, 129.0, 128.8, 128.2, 126.5, 66.2, 47.8, 45.8, 42.9. HRMS (DART) m/z: [M + H]+ calcd for C23H19BrNO4, 452.0492; found, 452.0487.

2-(1H-Indol-3-yl)ethyl 4-Bromobenzoate (4).

79 mg; 23% yield. Physical state: yellow oil. Rf = 0.5 (silica gel, 1:3 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.05 (s, 1H), 7.92–7.88 (m, 2H), 7.70–7.68 (m, 2H), 7.60–7.55 (m, 2H), 7.38 (d, J = 8.1 Hz, 1H), 7.25–7.21 (m, 1H), 7.16 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H), 7.10–7.08 (m, 1H), 4.61 (t, J = 7.1 Hz, 2H), 3.25 (td, J = 7.1, 0.9 Hz, 2H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 165.9, 136.2, 131.6, 131.1, 129.3, 128.0, 127.4, 122.2, 122.0, 119.5, 118.7, 112.0, 111.2, 65.3, 24.8. HRMS (DART) m/z: [M + Na]+ calcd for C17H14BrNO2Na, 366.0100; found, 366.0123.

2-(Phenylthio)ethyl 4-Bromobenzoate (5).

159 mg; 94% yield. Physical state: yellow oil. Rf = 0.5 (silica gel, 1:10 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 7.82–7.79 (m, 2H), 7.57–7.54 (m, 2H), 7.45–7.41 (m, 2H), 7.33–7.28 (m, 2H), 7.24–7.20 (m, 1H), 4.48 (t, J = 6.8 Hz, 2H), 3.28 (t, J = 6.8 Hz, 2H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 165.6, 135.1, 131.7, 131.2, 130.1, 129.1, 128.8, 128.2, 126.7, 63.9, 32.6. HRMS (DART) m/z: [M + H]+ calcd for C15H14BrO2S, 336.9892; found, 336.9886.

4-(Benzyloxy)butyl 4-Bromobenzoate (6).

151 mg; 83% yield. Physical state: white solid. Rf = 0.5 (silica gel, 1:10 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 7.91–7.87 (m, 2H), 7.63–7.55 (m, 2H), 7.37–7.32 (m, 4H), 7.31–7.26 (m, 1H), 4.52 (s, 2H), 4.34 (t, J = 6.5 Hz, 2H), 3.54 (t, J = 6.2 Hz, 2H), 1.90–1.86 (m, 2H), 1.79–1.85 (m, 2H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 165.9, 138.4, 131.7, 131.1, 129.3, 128.4, 127.9, 127.6, 127.6, 73.0, 69.7, 65.1, 26.4, 25.6. HRMS (DART) m/z: [M + NH4]+ calcd for C18H23BrNO3, 380.0856; found, 380.0862.

(Z)-Octadec-9-en-1-yl 4-Bromobenzoate (7).

201 mg; 88% yield. Physical state: yellow oil. Rf = 0.5 (silica gel, 1:10 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 7.91–7.88 (m, 2H), 7.59–7.56 (m, 2H), 5.36–5.33 (m, 2H), 4.30 (t, J = 6.7 Hz, 2H), 2.04–1.99 (m, 4H), 1.79–1.72 (m, 2H), 1.45–1.26 (m, 23H), 0.88 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 165.9, 131.6, 131.1, 130.0, 129.7, 129.4, 127.9, 65.4, 31.9, 29.8, 29.7, 29.6, 29.5, 29.5, 29.4, 29.2, 29.2, 29.2, 28.6, 27.2, 26.0, 22.7, 14.1. HRMS (DART) m/z: [M + H]+ calcd for C25H40BrO2, 451.2206; found, 451.2200.

Benzo[d][1,3]dioxol-5-ylmethyl 4-Bromobenzoate (8).

160 mg; 95% yield. Physical state: white solid. Rf = 0.5 (silica gel, 1:5 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 7.92–7.89 (m, 2H), 7.58–7.54 (m, 2H), 6.93–6.90 (m, 2H), 6.80 (dd, J = 7.7, 0.6 Hz, 1H), 5.97 (s, 2H), 5.24 (s, 2H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 165.7, 147.8, 147.7, 131.7, 131.2, 129.4, 129.0, 128.1, 122.3, 109.0, 108.3, 101.2, 66.9. HRMS (DART) m/z: [M + NH4]+ calcd for C15H15BrNO4, 352.0179; found, 352.0163.

Hex-5-yn-1-yl 4-Bromobenzoate (9).

120 mg; 85% yield. Physical state: colorless oil. Rf = 0.5 (silica gel, 1:10 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 7.90–7.87 (m, 2H), 7.58–7.54 (m, 2H), 4.33 (td, J = 6.5, 0.9 Hz, 2H), 2.27 (td, J = 7.0, 2.7 Hz, 2H), 1.97 (t, J = 2.7 Hz, 1H), 1.93–1.86 (m, 2H), 1.72–1.64 (m, 2H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 165.8, 131.6, 131.0, 129.2, 127.9, 83.71, 68.8, 64.7, 27.7, 25.0, 18.1. HRMS (DART) m/z: [M + H]+ calcd for C13H14BrO2, 281.0172; found, 281.0175.

6-Azidohexyl 4-Bromobenzoate (10).

100 mg; 61% yield. Physical state: colorless oil. Rf = 0.5 (silica gel, 1:2 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 7.91–7.87 (m, 2H), 7.59–7.56 (m, 2H), 4.31 (t, J = 6.6 Hz, 2H), 3.27 (t, J = 6.8 Hz, 2H), 1.80–1.74 (m, 2H), 1.64–1.59 (m, 2H), 1.49–1.43 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 165.9, 131.7, 131.0, 129.3, 127.9, 65.1, 51.3, 28.7, 28.5, 26.4, 25.6. HRMS (DART) m/z: [M + NH4]+ calcd for C13H20BrN4O2, 343.0764; found, 343.0773.

((4S,6S)-6-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 4-Bromobenzoate (11).

60 mg; 26% yield. Physical state: colorless oil. Rf = 0.5 (silica gel, 4:1 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 9.69 (s, 1H), 7.90–7.88 (m, 2H), 7.59–7.57 (m, 2H), 7.27–7.25 (m, 1H), 5.69 (d, J = 8.1 Hz, 1H), 5.61 (d, J = 1.7 Hz, 1H), 5.10 (dd, J = 6.4, 1.7 Hz, 1H), 4.95 (dd, J = 6.4, 4.2 Hz, 1H), 4.58–4.54 (m, 1H), 4.47–4.45 (m, 1H), 1.58 (s, 3H), 1.37 (s, 3H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 165.4, 163.6, 150.0, 142.7, 131.8, 131.7, 131.2, 131.2, 128.5, 128.4, 114.6, 102.6, 95.6, 85.7, 84.6, 81.2, 64.7, 60.4, 27.1, 25.3, 14.2. HRMS (LC-MS-TOF) m/z: [M + H]+ calcd for C19H20BrN2O7, 467.0448; found, 467.0449.

6-((4-Bromophenyl)thio)hexyl Benzoate (12).

187 mg, 95% yield. Physical state: colorless oil. Rf = 0.5 (silica gel, 1:10 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.05–8.02 (m, 2H), 7.58–7.54 (m, 1H), 7.46–7.43 (m, 2H), 7.42–7.37 (m, 2H), 7.19–7.16 (m, 2H), 4.31 (t, J = 6.6 Hz, 2H), 2.90 (t, J = 6.6 Hz, 2H), 1.80–1.73 (m, 2H), 1.70–1.63 (m, 2H), 1.54–1.44 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 166.6, 136.0, 132.8, 131.8, 130.4, 130.4, 129.5, 128.3, 119.5, 64.8, 33.6, 28.8, 28.6, 28.4, 25.6. HRMS (DART) m/z: [M + H]+ calcd for C19H22BrO2S, 393.0518; found, 393.0516.

6-(Benzo[d]thiazol-2-ylthio)hexyl Benzoate (13).

186 mg; 97% yield. Physical state: yellow oil. Rf = 0.5 (silica gel, 1:3 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.05–8.03 (m, 2H), 7.86 (dt, J = 8.0, 1.0 Hz, 1H), 7.74 (dt, J = 8.0, 1.0 Hz, 1H), 7.56–7.52 (m, 1H), 7.44–7.37 (m, 3H), 7.30–7.25 (m, 1H), 4.32 (t, J = 6.6 Hz, 2H), 3.40–3.25 (m, 2H), 1.90–1.76 (m, 4H), 1.59–1.49 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 167.1, 166.6, 153.3, 135.1, 132.8, 130.3, 129.5, 128.3, 126.0, 124.0, 121.4, 120.9, 64.8, 33.4, 29.1, 28.5, 28.3, 25.5. HRMS (DART) m/z: [M + H]+ calcd for C20H22NO2S2, 372.1086; found, 372.1102.

6-(Pyrimidin-2-ylthio)hexyl Benzoate (14).

155 mg; 88% yield. Physical state: colorless oil. Rf = 0.5 (silica gel, 1:3 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.50 (d, J = 4.9 Hz, 2H), 8.06–8.03 (m, 2H), 7.57–7.53 (m, 1H), 7.46–7.41 (m, 2H), 6.94 (t, J = 4.8 Hz, 1H), 4.32 (t, J = 6.6 Hz, 2H), 3.16 (t, J = 7.2 Hz, 2H), 1.83–1.74 (m, 4H), 1.58–1.49 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 172.7, 166.7, 157.2, 132.8, 130.5, 129.5, 128.3, 116.3, 65.0, 30.7, 29.0, 28.6, 28.5, 25.7. HRMS (DART) m/z: [M + H]+ calcd for C17H21N2O2S, 317.1318; found, 317.1340.

6-((4,5-Dihydrothiazol-2-yl)thio)hexyl Benzoate (15).

155 mg; 95% yield. Physical state: colorless oil. Rf = 0.5 (silica gel, 1:3 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.05–8.02 (m, 2H), 7.57–7.53 (m, 1H), 7.46–7.42 (m, 2H), 4.31 (t, J = 6.6 Hz, 2H), 4.20 (t, J = 8.0 Hz, 2H), 3.37 (t, J = 7.9 Hz, 2H), 3.11 (t, J = 7.2 Hz, 2H), 1.79–1.71 (m, 4H), 1.50–1.40 (m, 4H). 13C NMR (101 MHz, CDCl3): δ 166.6, 165.7, 132.8, 130.4, 129.5, 128.3, 64.9, 64.3, 35.3, 32.6, 29.2, 28.6, 28.4, 25.6. HRMS (DART) m/z: [M + H]+ calcd for C16H22NO2S2, 324.1086; found, 324.1105.

6-((4-Methyl-2-oxo-2H-chromen-7-yl)thio)hexyl Benzoate (16).

195 mg; 91% yield. Physical state: yellow oil. Rf = 0.5 (silica gel, 1:3 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.04–8.01 (m, 2H), 7.56–7.52 (m, 1H), 7.45–7.40 (m, 3H), 7.14–7.12 (m, 2H), 6.19 (q, J = 1.2 Hz, 1H), 4.31 (t, J = 6.6 Hz, 2H), 2.99 (t, J = 7.2 Hz, 2H), 2.38 (d, J = 1.3 Hz, 3H), 1.80–1.70 (m, 5H), 1.60–1.48 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 166.6, 160.6, 153.8, 152.2, 143.5, 132.8, 130.3, 129.5, 128.3, 124.5, 122.9, 117.0, 113.9, 113.7, 64.8, 32.0, 28.5, 28.5, 28.5, 25.6, 18.5. HRMS (LC-MS-TOF) m/z: [M + H]+ calcd for C23H25O4S, 397.1468; found, 397.1485.

6-((1-Methyl-1H-imidazol-2-yl)thio)hexyl Benzoate (17).

150 mg; 94% yield. Physical state: colorless oil. Rf = 0.5 (silica gel, 1:1 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.04–8.01 (m, 2H), 7.56–7.52 (m, 1H), 7.45–7.40 (m, 2H), 7.04 (d, J = 1.3 Hz, 1H), 6.90 (d, J = 1.3 Hz, 1H), 4.29 (t, J = 6.6 Hz, 2H), 3.59 (s, 3H), 3.05 (t, J = 7.2 Hz, 2H), 1.77–1.65 (m, 4H), 1.50–1.43 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 166.6, 141.9, 132.8, 130.4, 129.4, 129.2, 128.3, 122.0, 64.8, 34.1, 33.1, 29.6, 28.5, 28.2, 25.6. HRMS (DART) m/z: [M + H]+ calcd for C17H23N2O2S, 319.1475; found, 319.1484.

6-((1H-Benzo[d]imidazol-2-yl)thio)hexyl Benzoate (18).

165 mg; 89% yield. Physical state: yellow solid. Rf = 0.5 (silica gel, 1:3 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 10.75 (s, 1H), 8.05–8.02 (m, 2H), 7.56–7.51 (m, 2H), 7.45–7.40 (m, 2H), 7.20–7.16 (m, 2H), 4.28 (t, J = 6.6 Hz, 2H), 3.31 (t, J = 7.3 Hz, 2H), 1.80–1.67 (m, 4H), 1.49–1.37 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 166.8, 150.6, 132.9, 130.3, 129.5, 128.3, 122.2, 64.9, 32.5, 29.4, 28.5, 28.2, 25.5. HRMS (DART) m/z: [M + H]+ calcd for C20H23N2O2S, 355.1475; found, 355.1488.

6-(Benzo[d]oxazol-2-ylthio)hexyl Benzoate (19).

161 mg; 90% yield. Physical state: white solid. Rf = 0.5 (silica gel, 1:6 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.05–8.03 (m, 2H), 7.61–7.58 (m, 1H), 7.57–7.53 (m, 1H), 7.46–7.41 (m, 3H), 7.30–7.21 (m, 2H), 4.33 (t, J = 6.6 Hz, 2H), 3.3 (t, J = 7.2 Hz, 2H), 1.92–1.77 (m, 4H), 1.62–1.50 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 166.6, 165.1, 151.8, 142.0, 132.8, 130.4, 129.5, 128.3, 124.2, 123.8, 118.3, 109.8, 64.9, 32.1, 29.1, 28.6, 28.3, 25.6. HRMS (DART) m/z: [M + H]+ calcd for C20H22NO3S, 356.1315; found, 356.1346.

6-((4-Aminopyrimidin-2-yl)thio)hexyl Benzoate (20).

155 mg; 93% yield. Physical state: white solid. Rf = 0.5 (silica gel, 1:1 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.05–8.00 (m, 3H), 7.56–7.52 (m, 1H), 7.45–7.40 (m, 2H), 6.09 (d, J = 5.8 Hz, 1H), 5.05 (s, 2H), 4.31 (t, J = 6.6 Hz, 2H), 3.10–3.07 (m, 2H), 1.93–1.70 (m, 4H), 1.53–1.46 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 171.5, 166.7, 162.3, 155.9, 132.8, 130.4, 129.5, 128.3, 100.8, 65.0, 30.4, 29.2, 28.5, 28.4, 25.6. HRMS (DART) m/z: [M + H]+ calcd for C17H22N3O2S, 332.1427; found, 332.1459.

6-(Pyridin-2-ylthio)hexyl Benzoate (21).

146 mg; 90% yield. Physical state: colorless oil. Rf = 0.5 (silica gel, 1:6 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.41 (dd, J = 5.0, 1.9 Hz, 1H), 8.06–8.03 (m, 2H), 7.57–7.52 (m, 1H), 7.47–7.41 (m, 3H), 7.15 (dt, J = 8.1, 1.0 Hz, 1H), 6.95 (ddd, J = 7.4, 5.0, 1.1 Hz, 1H), 4.31 (t, J = 6.6 Hz, 2H), 3.18 (t, J = 7.2 Hz, 2H), 1.82–1.69 (m, 4H), 1.58–1.45 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 166.6, 159.4, 149.4, 135.8, 132.8, 130.4, 129.5, 128.3, 122.2, 119.2, 64.9, 29.9, 29.2, 28.6, 28.5, 25.7. HRMS (DART) m/z: [M + H]+ calcd for C18H22NO2S, 316.1366; found, 316.1373.

6-((Furan-2-ylmethyl)thio)hexyl Benzoate (22).

Physical state: yellow oil. Rf = 0.5 (silica gel, 1:10 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.05–8.03 (m, 2H), 7.57–7.53 (m, 1H), 7.46–7.41 (m, 2H), 7.34 (dd, J = 1.9, 0.9 Hz, 1H), 6.29 (dd, J = 3.2, 1.8 Hz, 1H), 6.17–6.15 (m, 1H), 4.31 (t, J = 6.6 Hz, 2H), 3.70 (d, J = 0.7 Hz, 2H), 2.51 (d, J = 7.2, 2H), 1.79–1.74 (m, 2H), 1.61–1.57 (m, 2H), 1.48–1.42 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 166.6, 151.8, 142.0, 132.8, 130.4, 129.5, 128.3, 110.3, 107.2, 64.9, 31.6, 29.0, 28.6, 28.4, 28.3, 25.6. HRMS (DART) m/z: [M + NH4]+ calcd for C18H26NO3S, 336.1628; found, 336.1645.

6-(Cyclohexylthio)hexyl Benzoate (23).

146 mg; 91% yield. Physical state: colorless oil. Rf = 0.5 (silica gel, 1:15 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.05–8.03 (m, 2H), 7.57–7.53 (m, 1H), 7.46–7.41 (m, 2H), 4.31 (t, J = 6.6 Hz, 2H), 2.66–2.59 (m, 1H), 2.54 (t, J = 7.2 Hz, 2H), 2.03–1.91 (m, 1H), 1.81–1.73 (m, 4H), 1.64–1.57 (m, 4H), 1.51–1.43 (m, 4H), 1.41–1.16 (m, 6H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 166.6, 132.8, 130.5, 129.5, 128.3, 64.9, 43.5, 42.7, 33.7, 33.2, 30.0, 29.9, 28.6, 26.1, 26.0, 25.9, 25.7. HRMS (DART) m/z: [M + NH4]+ calcd for C19H32NO2S, 338.2148; found, 338.2178.

6-(Benzoylthio)hexyl Benzoate (24).

134 mg; 78% yield. Physical state: colorless oil. Rf = 0.5 (silica gel, 1:10 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.06–8.03 (m, 2H), 7.98–7.95 (m, 2H), 7.58–7.53 (m, 2H), 7.47–7.41 (m, 4H), 4.33 (t, J = 6.6 Hz, 2H), 3.09 (t, J = 7.2 Hz, 2H), 1.83–1.68 (m, 4H), 1.56–1.46 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 192.0, 166.6, 137.2, 133.2, 132.8, 130.4, 129.5, 128.5, 128.3, 127.2, 64.9, 29.5, 28.9, 28.6, 28.5, 25.6. HRMS (DART) m/z: [M + NH4]+ calcd for C20H26NO3S, 360.1628; found, 360.1654.

6-(1H-Benzo[d]imidazol-1-yl)hexyl Benzoate (25).

94 mg; 58% yield. Physical state: white solid. Rf = 0.5 (silica gel, 3:1 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.05–8.01 (m, 2H), 7.88 (s, 1H), 7.85–7.78 (m, 1H), 7.57–7.46 (m, 1H), 7.46–7.37 (m, 2H), 7.32–7.25 (m, 2H), 4.30 (t, J = 6.5 Hz, 2H), 4.17 (t, J = 7.1 Hz, 2H), 1.95–1.88 (m, 2H), 1.79–1.72 (m, 2H), 1.53–1.39 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 166.56, 143.9, 142.8, 133.7, 132.9, 130.3, 129.4, 128.3, 122.8, 122.0, 120.4, 109.5, 64.6, 44.9, 29.7, 28.5, 26.5, 25.6. HRMS (DART) m/z: [M + H]+calcd for C20H23N2O2, 323.1754; found, 323.1759.

6-(1,3-Dioxoisoindolin-2-yl)hexyl Benzoate (26).

116 mg; 66% yield. Physical state: white solid. Rf = 0.5 (silica gel, 1:3 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.04–8.01 (m, 2H), 7.83–7.80 (m, 2H), 7.71–7.68 (m, 2H), 7.56–7.51 (m, 1H), 7.44–7.40 (m, 2H), 4.29 (t, J = 6.6 Hz, 2H), 3.69 (t, J = 7.2 Hz, 2H), 1.80–1.67 (m, 4H), 1.54–1.37 (m, 4H). 13C NMR (101 MHz, CDCl3): δ 168.4, 166.6, 133.8, 132.7, 132.1, 130.4, 129.5, 128.3, 123.1, 64.8, 37.8, 28.6, 28.5, 26.5, 25.6. HRMS (DART) m/z: [M + NH4]+ calcd for C21H25N2O4, 369.1809; found, 369.1826.

6-(Indolin-1-yl)hexyl Benzoate (27).

122 mg; 75% yield. Physical state: colorless oil. Rf = 0.5 (silica gel, 1:5 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.09–8.06 (m, 2H), 7.60–7.55 (m, 1H), 7.48–7.43 (m, 2H), 7.10–7.05 (m, 2H), 6.67–6.63 (m, 1H), 6.47 (dd, J = 7.6, 1.1 Hz, 1H), 4.36 (t, J = 6.6 Hz, 2H), 3.35 (t, J = 8.3 Hz, 2H), 3.08 (t, J = 7.6 Hz, 2H), 2.97 (t, J = 8.3 Hz, 2H), 1.86–1.79 (m, 2H), 1.70–1.63 (m, 2H), 1.58–1.45 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 166.6, 152.7, 132.8, 130.4, 129.9, 129.5, 128.3, 127.2, 124.3, 117.2, 106.7, 64.9, 53.0, 49.1, 28.7, 28.5, 27.3, 26.7, 25.9. HRMS (DART) m/z: [M + H]+ calcd for C21H26NO2, 324.1958; found, 324.1987.

6-Morpholinohexyl Benzoate (28).

90 mg; 61% yield. Physical state: yellow oil. Rf = 0.5 (silica gel, 8:1 DCM/MeOH). 1H NMR (400 MHz, CDCl3): δ 8.05–8.01 (m, 2H), 7.57–7.52 (m, 1H), 7.45–7.41 (m, 2H), 4.31 (t, J = 6.6 Hz, 2H), 3.70 (t, J = 4.5 Hz, 4H), 2.43–2.41 (m, 4H), 2.34–2.30 (m, 2H), 1.81–1.74 (m, 2H), 1.53–1.35 (m, 6H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 166.6, 132.8, 130.4, 129.5, 128.3, 67.0, 64.9, 64.7, 59.0, 53.8, 28.6, 27.1, 26.4, 26.0. HRMS (DART) m/z: [M + H]+ calcd for C17H26NO3, 292.1907; found, 292.1933.

6-((4-Iodophenyl)amino)hexyl Benzoate (29).

115 mg; 54% yield. Physical state: yellow solid. Rf = 0.5 (silica gel, 1:3 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.06–8.03 (m, 2H), 7.58–7.54 (m, 1H), 7.46–7.39 (m, 4H), 6.38–6.36 (m, 2H), 4.33 (t, J = 6.6 Hz, 2H), 3.66 (s, 1H), 3.10–3.06 (m, 2H), 1.81–1.77 (m, 2H), 1.65–1.60 (m, 2H), 1.51–1.45 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 166.6, 161.1, 147.9, 137.7, 132.8, 130.4, 129.5, 128.3, 114.8, 77.5, 64.82, 43.6, 29.2, 28.6, 26.7, 25.8. HRMS (DART) m/z: [M + H]+ calcd for C19H23INO2, 424.0768; found, 424.0795.

6-(Methyl(3-phenyl-3-(4-(trifluoromethyl)phenoxy)propyl)-amino)hexyl Benzoate (30).

210 mg; 82% yield. Physical state: colorless oil. Rf = 0.5 (silica gel, 8:1 DCM/MeOH). 1H NMR (400 MHz, CDCl3): δ 8.05–8.03 (m, 2H), 7.56–7.52 (m, 1H), 7.45–7.40 (m, 4H), 7.35–7.30 (m, 4H), 7.27–7.24 (m, 1H), 6.91–6.89 (m, 2H), 5.29 (dd, J = 8.4, 4.7 Hz, 1H), 4.29 (t, J = 6.7 Hz, 2H), 2.58–2.51 (m, 1H), 2.45–2.39 (m, 1H), 2.35–2.28 (m, 2H), 2.21 (s, 3H), 2.19–2.11 (m, 1 H), 1.96–1.92 (m, 1H), 1.75–1.68 (m, 2H), 1.48–1.29 (m, 6H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 166.6, 160.7, 141.3, 132.8, 130.5, 129.5, 129.0, 128.7, 128.3, 127.7, 126.68 (q, J = 3.8 Hz), 125.8, 125.7, 125.6, 122.6 (q, J = 32.0 Hz), 115.6, 78.4, 65.0, 57.8, 53.6, 42.2, 36.6, 28.6, 27.3, 27.1, 26.0. HRMS (LC-MS-TOF) m/z: [M + H]+ calcd for C30H35F3NO3, 514.2564; found, 514.2593.

6-Azidohexyl Benzoate (31).

120 mg; 96% yield. Physical state: colorless oil. Rf = 0.5 (silica gel, 1:10 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.06–8.03 (m, 2H), 7.57–7.53 (m, 1H), 7.46–7.41 (m, 2H), 4.32 (t, J = 6.6 Hz, 2H), 3.27 (t, J = 6.9 Hz, 2H), 1.80–1.75 (m, 2H), 1.67–1.60 (m, 2H), 1.51–1.43 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 166.6, 132.8, 130.4, 129.5, 128.3, 64.8, 51.3, 28.7, 28.6, 26.4, 25.6. HRMS (DART) m/z: [M + NH4]+ calcd for C13H21N4O2, 265.1659; found, 265.1685.

6-Cyanohexyl Benzoate (32).

60 mg; 52% yield. Physical state: white solid; Rf = 0.5 (silica gel, 1:1 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.05–8.02 (m, 2H), 7.57–7.53 (m, 1H), 7.46–7.41 (m, 2H), 4.32 (t, J = 6.5 Hz, 2H), 2.34 (t, J = 7.1 Hz, 2H), 1.82–1.75 (m, 2H), 1.72–1.65 (m, 2H), 1.56–1.46 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 166.5, 132.8, 130.3, 129.4, 128.3, 119.6, 64.6, 28.4, 28.3, 25.3, 25.2, 17.0. HRMS (DART) m/z: [M + H]+ calcd for C14H18NO2, 232.1332; found, 232.1346.

6-(4-Bromophenoxy)hexyl Benzoate (33).

147 mg; 78% yield. Physical state: colorless oil. Rf = 0.5 (silica gel, 1:8 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.06–8.03 (m, 2H), 7.58–7.54 (m, 1H), 7.46–7.41 (m, 2H), 7.39–7.32 (m, 2H), 6.78–6.74 (m, 2H), 4.34 (t, J = 6.6 Hz, 2H), 3.93 (t, J = 6.4 Hz, 2H), 1.85–1.76 (m, 4H), 1.60–1.45 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 166.6, 158.2, 132.8, 132.2, 130.4, 129.5, 128.3, 116.3, 112.6, 68.0, 64.9, 29.0, 28.6, 25.8, 25.7. HRMS (DART) m/z: [M + NH4]+ calcd for C19H25NBrO3, 394.1012; found, 394.0996.

6-(4-Nitrophenoxy)hexyl Benzoate (34).

150 mg; 87% yield. Physical state: white solid. Rf = 0.5 (silica gel, 1:3 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.19–8.15 (m, 2H), 8.06–8.01 (m, 2H), 7.57–7.53 (m, 1H), 7.45–7.40 (m, 2H), 6.94–6.89 (m, 2H), 4.34 (t, J = 6.6 Hz, 2H), 4.05 (t, J = 6.4 Hz, 2H), 1.87–1.80 (m, 4H), 1.58–1.53 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 166.6, 164.1, 141.3, 132.8, 130.3, 129.5, 128.3, 125.8, 114.3, 68.6, 64.7, 28.8, 28.6, 25.7, 25.6. HRMS (DART) m/z: [M + NH4]+ calcd for C19H25N2O5, 361.1758; found, 361.1756.

6-((5-Iodopyridin-2-yl)oxy)hexyl Benzoate (35).

105 mg; 49% yield. Physical state: white solid. Rf = 0.3 (silica gel, 1:1 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.04–8.01 (m, 2H), 7.57–7.52 (m, 1H), 7.46–7.38 (m, 4H), 6.38–6.36 (m, 1H), 4.30 (t, J = 6.5 Hz, 2H), 3.7 (t, J = 7.2 Hz, 2H), 1.81–1.71 (m, 4H), 1.53–1.37 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 166.6, 160.9, 146.6, 142.3, 132.8, 130.3, 129.5, 128.3, 122.9, 64.7, 64.0, 49.8, 29.2, 28.5, 26.2, 25.7. HRMS (DART) m/z: [M + H]+ calcd for C18H21INO3, 426.0561; found, 426.0556.

6-((5-Bromopyridin-2-yl)oxy)hexyl Benzoate (36).

131 mg; 69% yield. Physical state: yellow oil. Rf = 0.5 (silica gel, 3:1 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.04–8.01 (m, 2H), 7.56–7.52 (m, 1H), 7.45–7.41 (m, 2H), 7.37–7.30 (m, 2H), 6.47 (dd, J = 9.6, 0.6 Hz, 1H), 4.30 (t, J = 6.6 Hz, 2H), 3.88 (t, J = 7.2 Hz, 2H), 1.81–1.72 (m, 4H), 1.53–1.39 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 166.6, 160.9, 146.6, 142.3, 132.8, 130.3, 129.5, 128.3, 122.9, 64.7, 64.0, 49.8, 29.2, 28.5, 26.2, 25.7. HRMS (DART) m/z: [M + H]+ calcd for C18H21BrNO3, 378.0699; found, 378.0706.

6-((2-Oxo-2H-chromen-7-yl)oxy)hexyl Benzoate (37).

137 mg; 74% yield. Physical state: colorless oil. Rf = 0.5 (silica gel, 1:2 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.04–8.02 (m, 2H), 7.62 (dd, J = 9.5, 0.6 Hz, 1H), 7.57–7.52 (m, 1H), 7.45–7.40 (m, 2H), 7.34 (d, J = 8.5 Hz, 1H), 6.83–6.78 (m, 2H), 6.23 (d, J = 9.5 Hz, 1H), 4.34 (t, J = 6.6 Hz, 2H), 4.01 (t, J = 6.4 Hz, 2H), 1.86–1.80 (m, 4H), 1.57–1.52 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 166.6, 162.3, 161.2, 155.9, 143.4, 132.8, 130.4, 129.5, 128.7, 128.3, 112.9, 112.4, 101.3, 68.4, 64.8, 28.8, 28.6, 25.8, 25.7. HRMS (LC-MS-TOF) m/z: [M + H]+ calcd for C22H23O5, 367.1540; found, 367.1556.

6-((4-Oxo-2-phenyl-4H-chromen-7-yl)oxy)hexyl Benzoate (38).

200 mg; 90% yield. Physical state: white solid. Rf = 0.5 (silica gel, 1:1 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.10 (d, J = 8.7 Hz, 1H), 8.05–8.01 (m, 2H), 7.89–7.86 (m, 2H), 7.55–7.47 (m, 4H), 7.43–7.39 (m, 2H), 6.96–6.92 (m, 2H), 6.73 (s, 1H), 4.34 (t, J = 6.6 Hz, 2H), 4.06 (t, J = 6.4 Hz, 2H), 1.89–1.80 (m, 4H), 1.59–1.54 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 177.7, 166.5, 163.6, 162.8, 157.9, 132.8, 131.8, 131.3, 130.3, 129.4, 128.9, 128.2, 126.9, 126.0, 117.6, 114.6, 107.4, 100.8, 68.4, 64.7, 28.8, 28.6, 25.7, 25.6. HRMS (LC-MS-TOF) m/z: [M + H]+ calcd for C28H27O5, 443.1853; found 443.1874.

6-(Quinolin-6-yloxy)hexyl Benzoate (39).

140 mg; 80% yield. Physical state: yellow oil. Rf = 0.3 (silica gel, 1:1 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.76 (dd, J = 4.3, 1.7 Hz, 1H), 8.06–7.97 (m, 4H), 7.56–7.52 (m, 1H), 7.44–7.41 (m, 2H), 7.37–7.32 (m, 2H), 7.05 (d, J = 2.8 Hz, 1H), 4.35 (t, J = 6.6 Hz, 2H), 4.09 (t, J = 6.4 Hz, 2H), 1.91–1.79 (m, 4H), 1.61–1.56 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 166.7, 157.2, 147.8, 144.4, 134.7, 132.8, 132.8, 130.8, 130.4, 129.5, 129.3, 128.3, 122.5, 121.3, 105.8, 68.0, 64.9, 29.0, 28.7, 25.8, 25.8. HRMS (LC-MS-TOF) m/z: [M + Na]+ calcd for C22H23NO3Na, 372.1570; found, 372.1587.

6-(Pyridin-4-yloxy)hexyl Benzoate (40).

105 mg; 70% yield. Physical state: yellow oil. Rf = 0.5 (silica gel, 10:1 DMC/MeOH). 1H NMR (400 MHz, CDCl3): δ 8.05–8.02 (m, 2H), 7.59–7.55 (m, 1H), 7.47–7.42 (m, 2H), 7.29–7.25 (m, 2H), 6.39–6.35 (m, 2H), 4.32 (t, J = 6.5 Hz, 2H), 3.77 (t, J = 7.2 Hz, 2H), 1.84–1.75 (m, 4H), 1.53–1.37 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 178.7, 166.5, 139.5, 132.9, 130.2, 129.4, 128.3, 118.7, 64.5, 56.8, 30.7, 28.4, 25.8, 25.5. HRMS (DART) m/z: [M + H]+ calcd for C18H22NO3, 300.1594; found, 300.1590.

6-((5-((3aS,4S,6aR)-2-Oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoyl)oxy)hexyl Benzoate (41).

189 mg; 84% yield. Physical state: yellow solid. Rf = 0.5 (silica gel, 10:1 DCM/MeOH). 1H NMR (400 MHz, CDCl3): δ 8.04–8.01 (m, 2H), 7.56–7.52 (m, 1H), 7.45–7.40 (m, 2H), 5.96 (s, 1H), 5.59 (s, 1H), 4.50–4.46 (m, 1H), 4.32–4.27 (m, 3H), 4.06 (t, J = 6.6 Hz, 2H), 3.16–3.11 m, 1H), 2.88 (dd, J = 12.8, 5.0 Hz, 1H), 2.72 (d, J = 12.8 Hz, 1H), 2.30 (t, J = 7.5 Hz, 2H), 1.81–1.61 (m, 8H), 1.49–1.38 (m, 6H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 173.8, 166.7, 163.7, 132.9, 130.4, 129.5, 128.4, 64.9, 64.3, 62.0, 60.1, 55.5, 40.5, 33.9, 28.6, 28.5, 28.4, 28.3, 25.7, 25.6, 24.8. HRMS (LC-MS-TOF) m/z: [M + H]+ calcd for C23H33N2O5S, 449.2105; found, 449.2123.

(E)-6-((2-Methylbut-2-enoyl)oxy)hexyl Benzoate (42).

98 mg; 64% yield. Physical state: colorless oil. Rf = 0.5 (silica gel, 1:8 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.05–8.02 (m, 2H), 7.57–7.53 (m, 1H), 7.46–7.41 (m, 2H), 6.85–6.82 (m, 1H), 4.32 (t, J = 6.6 Hz, 2H), 4.13 (t, J = 6.6 Hz, 2H), 1.84–1.75 (m, 8H), 1.74–1.67 (m, 2H), 1.52–1.44 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 168.2, 166.6, 136.9, 132.8, 130.4, 129.5, 128.7, 128.3, 64.9, 64.3, 28.6, 28.6, 25.8, 14.3, 12.0. HRMS (DART) m/z: [M + H]+ calcd for C18H25O4, 305.1747; found, 305.1760.

6-((2-Phenylacryloyl)oxy)hexyl Benzoate (43).

142 mg; 80% yield. Physical state: colorless oil. Rf = 0.5 (silica gel, 1:8 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.06–8.03 (m, 2H), 7.58–7.53 (m, 1H), 7.47–7.41 (m, 4H), 7.38–7.32 (m, 3H), 6.34 (d, J = 1.3 Hz, 1H), 5.88 (d, J = 1.3 Hz, 1H), 4.32 (t, J = 6.6 Hz, 2H), 4.24 (t, J = 6.6 Hz, 2H), 1.80–1.71 (m, 4H), 1.52–1.43 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 166.8, 166.6, 141.5, 136.7, 132.8, 132.8, 130.7, 130.4, 129.5, 128.3, 128.3, 128.3, 128.1, 128.0, 126.5, 65.0, 64.8, 28.6, 28.5, 25.7. HRMS (LC-MS-TOF) m/z: [M + Na]+ calcd for C22H24O4Na, 375.1567; found, 375.1576.

6-(2-(1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-acetoxy)hexyl Benzoate (44).

145 mg; 51% yield. Physical state: yellow oil. Rf = 0.5 (silica gel, 1:4 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.05–8.02 (m, 2H), 7.67–7.64 (m, 2H), 7.57–7.53 (m, 1H), 7.48–7.41 (m, 4H), 6.97 (d, J = 2.5 Hz, 1H), 6.86 (dd, J = 9.0, 0.5 Hz, 1H), 6.66 (dd, J = 9.0, 2.6 Hz, 1H), 4.29 (t, J = 6.6 Hz, 2H), 4.11 (t, J = 6.6 Hz, 2H), 3.83 (s, 3H), 3.65 (s, 2H), 2.39 (s, 3H), 1.74–1.62 (m, 4H), 1.46–1.37 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 170.9, 168.3, 166.6, 156.0, 139.2, 135.9, 133.9, 132.8, 131.1, 130.8, 130.6, 130.4, 129.5, 129.0, 128.3, 114.9, 112.6, 111.5, 101.4, 64.9, 64.8, 55.7, 30.4, 28.6, 28.5, 25.6, 25.6, 13.3. HRMS (DART) m/z: [M + NH4]+ calcd for C32H36ClN2O6, 579.2256; found, 579.2263.

6-(2-(5-Methoxy-2-methyl-1H-indol-3-yl)acetoxy)hexyl Benzoate (45).

81 mg; 38% yield. Physical state: colorless oil. Rf = 0.5 (silica gel, 1:4 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.06–8.03 (m, 2H), 7.83 (s, 1H), 7.58–7.54 (m, 1H), 7.47–7.42 (m, 2H), 7.13 (dd, J = 8.7, 0.6 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.76 (dd, J = 8.7, 2.4 Hz, 1H), 4.25 (t, J = 6.6 Hz, 2H), 4.07 (t, J = 6.5 Hz, 2H), 3.84 (s, 3H), 3.64 (s, 2H), 2.38 (s, 3H), 1.72–1.58 (m, 4H), 1.40–1.29 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 172.1, 166.7, 154.1, 133.4, 132.9, 130.4, 130.2, 129.5, 129.0, 128.4, 110.9, 104.6, 100.5, 64.9, 64.5, 55.9, 30.6, 28.6, 28.5, 25.6, 25.5, 11.8. HRMS (DART) m/z: [M + H]+ calcd for C25H30NO5, 424.2118; found, 424.2120.

6-(Benzoyloxy)hexyl Nicotinate (46).

120 mg; 73% yield. Physical state: white solid. Rf = 0.5 (silica gel, 1:1 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 9.22 (dd, J = 2.2, 0.9 Hz, 1H), 8.76 (dd, J = 4.9, 1.8 Hz, 1H), 8.28 (dt, J = 7.9, 2.0 Hz, 1H), 8.05–8.02 (m, 2H), 7.56–7.52 (m, 1H), 7.45–7.36 (m, 3H), 4.38–4.32 (m, 4H), 1.84–1.78 (m, 4H), 1.55–1.51 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 166.6, 165.3, 153.3, 150.9, 137.0, 132.8, 132.8, 130.4, 129.5, 128.3, 126.2, 123.2, 65.3, 64.8, 28.6, 28.6, 25.7, 25.7. HRMS (DART) m/z: [M + H]+ calcd for C19H22NO4, 328.1543; found, 328.1561.

6-(2-((1R,2S,4R)-Bicyclo[2.2.1]hept-5-en-2-yl)acetoxy)hexyl Benzoate (47).

138 mg; 77% yield. Physical state: colorless oil. Rf = 0.5 (silica gel, 1:10 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.05–8.03 (m, 2H), 7.57–7.53 (m, 1H), 7.46–7.41 (m, 2H), 6.14–6.08 (m, 2H), 4.32 (t, J = 6.6 Hz, 2H), 4.09 (t, J = 6.6, 2H), 3.03–3.01 (m, 1H), 2.92–2.89 (m, 1H), 2.23–2.19 (m, 1H), 1.93–1.89 (m, 1H), 1.82–1.75 (m, 2H), 1.71–1.64 (m, 2H), 1.53–1.42 (m, 5H), 1.38–1.32 (m, 2H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 176.3, 166.6, 138.0, 135.7, 132.8, 130.4, 129.5, 128.3, 64.9, 64.3, 46.6, 46.3, 43.2, 41.6, 30.3, 28.6, 28.6, 25.7, 25.7. HRMS (DART) m/z: [M + H]+ calcd for C22H29O4, 357.2060; found, 357.2055.

6-(Benzoyloxy)hexyl Furan-2-carboxylate (48).

127 mg; 80% yield. Physical state: colorless oil. Rf = 0.5 (silica gel, 1:10 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.05–8.02 (m, 2H), 7.57–7.52 (m, 2H), 7.45–7.41 (m, 2H), 7.16 (dd, J = 3.5, 0.9 Hz, 1H), 6.49 (dd, J = 3.5, 1.7 Hz, 1H), 4.34–4.29 (m, 4H), 1.81–1,77 (m, 4H), 1.53–1.49 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 166.6, 158.8, 146.2, 144.8, 132.8, 130.4, 129.5, 128.3, 117.7, 111.8, 64.8, 28.6, 28.6, 25.7, 25.6. HRMS (DART) m/z: [M + NH4]+ calcd for C18H24NO5, 334.1649; found, 334.1671.

6-(Benzoyloxy)hexyl 4-Bromobenzoate (49).

181 mg; 89% yield. Physical state: white solid. Rf = 0.5 (silica gel, 1:10 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.05–8.02 (m, 2H), 7.90–7.87 (m, 2H), 7.58–7.53 (m, 3H), 7.45–7.41 (m, 2H), 4.35–4.31 (m, 4H), 1.84–1.77 (m, 4H), 1.56–1.50 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 166.6, 165.9, 132.8, 131.7, 131.0, 130.4, 129.5, 129.3, 128.3, 127.9, 65.2, 64.8, 28.6, 28.6, 25.8, 25.7. HRMS (DART) m/z: [M + NH4]+ calcd for C20H25NBrO4, 422.0961; found, 422.0968.

6-(Henzoyloxy)hexyl Benzo[b]thiophene-3-carboxylate (50).

182 mg; 95% yield. Physical state: colorless oil. Rf = 0.5 (silica gel, 1:10 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.61–8.58 (m, 1H), 8.37 (s, 1H), 8.06–8.03 (m, 2H), 7.87 (dt, J = 8.0, 1.0 Hz, 1H), 7.56–7.52 (m, 1H), 7.49 (ddd, J = 8.3, 7.1, 1.2 Hz, 1H), 7.45–7.39 (m, 3H), 4.40–4.33 (m, 4H), 1.87–1.81 (m, 4H), 1.59–1.54 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 166.6, 162.8, 140.0, 136.7, 136.5, 132.8, 130.4, 129.5, 128.3, 127.3, 125.4, 125.0, 124.7, 122.5, 64.8, 64.6, 28.7, 28.6, 25.8, 25.8. HRMS (DART) m/z: [M + NH4]+ calcd for C22H26NO4S, 400.1577; found, 400.1594.

6-((3-(1-Methyl-1H-indol-3-yl)propanoyl)oxy)hexyl Benzoate (51).

152 mg; 74% yield. Physical state: colorless oil. Rf = 0.5 (silica gel, 1:4 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.06–8.04 (m, 2H), 7.61–7.54 (m, 2H), 7.47–7.42 (m, 2H), 7.30–7.27 (m, 1H), 7.24–7.20 (m, 1H), 7.13–7.09 (m, 1H), 6.87 (d, J = 0.9 Hz, 1H), 4.31 (t, J = 6.6 Hz, 2H), 4.09 (t, J = 6.6 Hz, 2H), 3.73 (s, 3H), 3.12–3.08 (m, 2H), 2.73–2.69 (m, 2H), 1.79–1.72 (m, 2H), 1.67–1.62 (m, 2H), 1.50–1.34 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 173.5, 166.6, 137.0, 132.8, 130.4, 129.5, 128.3, 127.6, 126.2, 121.5, 118.8, 118.7, 113.4, 109.1, 64.9, 64.3, 35.2, 32.6, 28.6, 28.5, 25.7, 25.6, 20.6. HRMS (DART) m/z: [M + H]+ calcd for C25H30NO4, 408.2169; found, 408.2190.

6-(Benzoyloxy)hexyl 1-Tosylpiperidine-4-carboxylate (52).

169 mg; 69% yield. Physical state: white solid. Rf = 0.5 (silica gel, 1:2 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.04–8.02 (m, 2H), 7.64–7.61 (m, 2H), 7.57–7.53 (m, 1H), 7.46–7.41 (m, 2H), 7.32–7.30 (m, 2H), 4.31 (t, J = 6.6 Hz, 2H), 4.05 (t, J = 6.6 Hz, 2H), 3.65–3.60 (m, 2H), 2.47–2.40 (m, 5H), 2.26–2.19 (m, 1H), 1.98–1.92 (m, 2H), 1.84–1.73 (m, 4H), 1.65–1.58 (m, 3H), 1.50–1.36 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 173.9, 166.6, 143.5, 133.1, 132.8, 130.3, 129.6, 129.5, 128.3, 127.6, 64.8, 64.5, 45.4, 40.1, 28.6, 28.4, 27.4, 25.6, 25.6, 21.5. HRMS (DART) m/z: [M + NH4]+ calcd for C26H37N2O6S, 505.2367, found 505.2378.

6-((Diphenylphosphoryl)oxy)hexyl Benzoate (53).

127 mg; 60% yield. Physical state: white solid. Rf = 0.5 (silica gel, 1:3 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.05–8.01 (m, 2H), 7.83–7.77 (m, 4H), 7.56–7.40 (m, 9H), 4.31–4.28 (m, 2H), 4.03 (q, J = 6.6 Hz, 2H), 1.79–1.72 (m, 4H), 1.49–1.44 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 166.9, 133.1, 133.1, 132.6, 132.4, 132.4, 131.9, 131.8, 131.2, 130.7, 129.8, 128.9, 128.7, 128.6, 65.2, 65.1, 65.1, 65.0, 63.0, 32.9, 30.8, 30.7, 28.9, 25.9, 25.6. HRMS (DART) m/z: [M + H]+ calcd for C25H28O4P, 423.1720; found, 423.1754.

6-(Benzoylthio)hexyl 2-(3-Benzoylphenyl)propanoate (54).

30 mg; 63% yield. Physical state: colorless oil. Rf = 0.5 (silica gel, 1:6 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 8.04–8.02 (m, 2H), 7.81–7.75 (m, 3H), 7.67 (dt, J = 7.6, 1.4 Hz, 1H), 7.60–7.53 (m, 3H), 7.50–7.41 (m, 5H), 4.28 (t, J = 6.6 Hz, 2H), 4.09 (t, J = 6.6 Hz, 2H), 3.79 (q, J = 7.2 Hz, 1H), 1.76–1.69 (m, 2H), 1.66–1.58 (m, 3H), 1.53 (d, J = 7.2 Hz, 3H), 1.46–1.28 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 196.4, 174.1, 166.6, 140.95, 137.85, 137.48, 133.23, 132.82, 132.46, 131.46, 130.40, 130.02, 129.49, 129.18, 129.0, 128.5, 128.5, 128.3, 128.3, 127.2, 64.8, 64.8, 45.4, 28.6, 28.4, 25.6, 25.5, 18.4. HRMS (DART) m/z: [M + NH4]+ calcd for C29H34NO4S, 492.2203; found, 492.2234.

6-Cyanohexyl 2-(3-Benzoylphenyl)propanoate (55).

25 mg; 68% yield. Physical state: colorless oil. Rf = 0.4 (silica gel, 1:4 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 7.81–7.78 (m, 2H), 7.76 (t, J = 1.8 Hz, 1H), 7.67 (dt, J = 7.6, 1.5 Hz, 1H), 7.62–7.58 (m, 1H), 7.54 (dt, J = 7.7, 1.6 Hz, 1H), 7.51–7.42 (m, 3H), 4.07 (t, J = 6.5, 2H), 3.79 (q, J = 7.2 Hz, 1H), 2.29 (t, J = 7.1 Hz, 2H), 1.63–1.56 (m, 4H), 1.54 (d, J = 7.2 Hz, 3H), 1.44–1.37 (m, 2H), 1.32–1.25 (m, 2H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 196.4, 174.0, 140.9, 137.9, 137.4, 132.5, 131.4, 130.0, 129.1, 129.0, 128.5, 128.3, 119.6, 64.6, 45.4, 28.2, 28.1, 25.1, 25.0, 18.3, 17.0. HRMS (DART) m/z: [M + NH4]+ calcd for C23H29N2O3, 381.2174; found, 381.2190.

6-((3-(3-Benzoylphenyl)but-1-en-2-yl)oxy)hexyl 5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoate (56).

51 mg; 87% yield. Physical state: white solid. Rf = 0.5 (silica gel, 10:1 DCM/MeOH). 1H NMR (400 MHz, CDCl3): δ 7.79–7.77 (m, 2H), 7.74 (t, J = 1.8 Hz, 1H), 7.66 (dt, J = 7.7, 1.4 Hz, 1H), 7.63–7.56 (m, 1H), 7.53 (dt, J = 7.8, 1.5 Hz, 1H), 7.49–7.41 (m, 3H), 5.72 (s, 1H), 5.37 (s, 1H), 4.52–4.46 (m, 1H), 4.31–4.27 (m, 1H), 4.06 (t, J = 6.6 Hz, 2H), 4.00 (t, J = 6.7 Hz, 2H), 3.78 (q, J = 7.2 Hz, 1H), 3.16–3.13 (m, 1H), 2.94 (s, 2H), 2.87 (d, J = 0.6 Hz, 2H), 2.29 (t, J = 7.5 Hz, 2H), 1.70–1.56 (m, 8H), 1.52 (d, J = 7.2 Hz, 4H), 1.46–1.41 (m, 2H), 1.32–1.24 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 196.5, 174.1, 173.7, 163.5, 162.5, 141.0, 137.8, 137.5, 132.5, 131.5, 130.0, 129.2, 129.0, 128.5, 128.3, 64.8, 64.3, 61.9, 60.1, 55.4, 45.4, 40.5, 36.5, 33.9, 28.5, 28.4, 28.3, 25.5, 25.4, 24.8, 18.4. HRMS (LC-MS-TOF) m/z: [M + H]+ calcd for C33H43N2O5S, 579.2950; found, 579.2928.

6-Azidohexyl 2-(3-Benzoylphenyl)propanoate (57).

30 mg; 79% yield. Physical state: colorless oil. Rf = 0.5 (silica gel, 1:8 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 7.81–7.78 (m, 2H), 7.76 (t, J = 1.8 Hz, 1H), 7.67 (dt, J = 7.6, 1.4 Hz, 1H), 7.62–7.57 (m, 1H), 7.54 (dt, J = 7.7, 1.6 Hz, 1H), 7.51–7.42 (m, 3H), 4.07 (t, J = 6.6 Hz, 2H), 3.79 (q, J = 7.2 Hz, 1H), 3.22 (t, J = 6.9 Hz, 2H), 1.63–1.50 (m, 7H), 1.38–1.25 (m, 4H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 196.4, 174.1, 141.0, 137.9, 137.5, 132.5, 131.5, 130.0, 129.2, 129.0, 128.5, 128.3, 64.7, 51.3, 45.4, 28.7, 28.4, 26.2, 25.4, 18.4. HRMS (DART) m/z: [M + NH4]+ calcd for C22H29N4O3, 397.2234; found, 397.2242.

N-(4-(Isopentyloxy)phenyl)acetamide (58).18

310 mg; 94% yield. Physical state: white solid. Rf = 0.5 (silica gel, 1:1 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 7.38–7.34 (m, 2H), 7.28 (s, 1H), 6.85–6.82 (m, 2H), 3.95 (t, J = 6.7 Hz, 2H), 2.14 (s, 3H), 1.86–1.79 (m, 1H), 1.65 (q, J = 6.7 Hz, 2H), 0.95 (d, J = 6.6 Hz, 6H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 168.2, 156.0, 130.8, 121.9, 114.7, 66.6, 38.0, 25.0, 24.3, 22.6.

Methyl 4-Butoxybenzoate (59).16

200 mg; 96% yield. Physical state: colorless oil. Rf = 0.5 (silica gel, 1:9 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 7.98–7.96 (m, 2H), 6.90–6.88 (m, 2H), 4.00 (t, J = 6.5 Hz, 2H), 3.87 (s, 3H), 1.81–1.73 (m, 2H), 1.52–1.46 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 166.8, 162.9, 131.5, 122.3, 114.0, 67.8, 51.7, 31.1, 19.1, 13.8.

4-Butoxyphenol (60).19

101 mg; 60% yield. Physical state: white solid. Rf = 0.5 (silica gel, 1:4 EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ 6.80–6.74 (m, 4H), 4.70 (s, 1H), 3.90 (t, J = 6.5 Hz, 2H), 1.77–1.70 (m, 2H), 1.52–1.43 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 153.3, 149.3, 116.0, 115.6, 68.4, 31.4, 19.2, 13.8.

Thiocarlide.

1H NMR (400 MHz, CDCl3): δ 7.53 (s, 2H), 7.28–7.24 (m, 4H), 6.93–6.89 (m, 4H), 3.98 (t, J = 6.6 Hz, 4H), 1.88–1.78 (m, 2H), 1.67 (q, J = 6.7 Hz, 4H), 0.96 (d, J = 6.6 Hz, 12H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 181.2, 158.3, 127.5, 115.2, 66.7, 37.9, 25.0, 22.5.

Pramoxine.

1H NMR (400 MHz, CDCl3): δ 6.82 (s, 4H), 3.96 (t, J = 6.3 Hz, 2H), 3.90 (t, J = 6.5 Hz, 2H), 3.71(t, J = 4.4 Hz, 4H), 2.52–2.49 (m, 2H), 2.47–2.43 (m, 4H), 1.97–1.90 (m, 2H), 1.77–1.70 (m, 2H), 1.50–1.45 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 153.3, 153.0, 115.4, 115.4, 68.3, 67.0, 66.7, 55.6, 53.7, 31.4, 26.6, 19.2, 13.8.

Butoxycaine.

1H NMR (400 MHz, CDCl3): δ 7.98–7.94 (m, 2H), 6.90–6.86 (m, 2H), 4.35 (t, J = 6.3 Hz, 2H), 3.99 (t, J = 6.5 Hz, 2H), 2.84 (t, J = 6.3 Hz, 2H), 2.62 (q, J = 7.1 Hz, 4H), 1.80–1.73 (m, 2H), 1.51–1.45 (m, 2H), 1.06 (t, J = 7.2 Hz, 6H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3): 13C{1H} δ 166.3, 162.9, 131.5, 122.4, 114.0, 67.8, 63.0, 51.0, 47.8, 31.1, 19.1, 13.8, 12.0.

Supplementary Material

Supplementary Material

ACKNOWLEDGMENTS

This work was supported by Colorado State University and the National Institute of General Medical Sciences of the National Institutes of Health under award number R35GM119702. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Footnotes

Supporting Information

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.9b03373.

Reaction development and optimization and NMR spectra (PDF)

Complete contact information is available at: https://pubs.acs.org/10.1021/acs.joc.9b03373

The authors declare no competing financial interest.

Contributor Information

Bin Liu, Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States;.

W. Zachary Elder, Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States.

Garret M. Miyake, Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States;.

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Supplementary Materials

Supplementary Material
NIHMS1580125-supplement-Supplementary_Material.pdf (17.9MB, pdf)

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