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. 2019 Dec 23;5(1):537–546. doi: 10.1021/acsomega.9b03107

Derivatives of DANPY (Dialkylaminonaphthylpyridinium), a DNA-Binding Fluorophore: Practical Synthesis of Tricyclic 2-Amino-6-bromonaphthalenes by Bucherer Reaction

Jason S Kingsbury †,*, Delwin L Elder ‡, Lewis E Johnson ‡, Brittany A Smolarski †, Hannah E Zeitler ‡, Emily G Armbruster †
PMCID: PMC6964316  PMID: 31956800

Abstract

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A simple and convergent way to synthesize 2-amino-6-bromonaphthalenes involves condensation of free secondary amines with the corresponding 2-naphthol under Bucherer conditions. The amination protocol relies on common Teflon-capped pressure flasks and has been used to modify the tertiary aminonaphthalene core of DANPY, a biocompatible chromophore shown to be safe and effective for staining a variety of cellular targets. Following a Suzuki reaction with pyridine 4-boronic acid, additional diversity is introduced upon N-alkylation to install the pyridinium cation. New DANPY derivatives and intermediates reported herein reflect the modularity of the dye nucleus, including the addition of groups useful for applications in membrane staining and DNA-based biophotonics.

Introduction

Dyes with nonlinear optical (NLO) activity1 are of interest for both photonic systems2 and a number of imaging techniques in living cells.3,4 The fluorescent dye molecule DANPY-15 is both NLO-active and biocompatible, possessing a range of other useful properties such as low toxicity, high photostability, and high sensitivity of its absorbance and fluorescence properties to its dielectric environment.5 First intended for use in DNA-based photonic systems,6,7 DANPY-1 was designed8 by joining structural features of the common intercalating agent ethidium bromide9,10 with those of the NLO-active dye DAST11,12 (Figure 1). The structure strikes a compromise among features that promote optical nonlinearity (a maximally extended π bridge) and affinity for DNA (a polycyclic pyridinium cation). DANPY-1 is similar to the zwitterionic membrane dye BNBP,13 but it lacks a captive anion and has shorter alkyl groups to reduce steric hindrance upon approach to DNA.

Figure 1.

Figure 1

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Various “push–pull” DNA dye molecules cited herein.

The core dialkylaminonaphthylpyridinium (DANPY) chromophore consists of a tertiary aromatic amine coupled to a para-substituted pyridinium cation. The dye’s optical properties are dominated by charge-transfer excitation in which naphthylamine acts as an electron donor and quaternary pyridinium acts as an acceptor. This “push–pull” asymmetry also introduces anharmonicity to the dye’s polarization response in an applied electric field, giving it a substantial dipole moment (μ) and first hyperpolarizability (β). A large hyperpolarizability is conducive to NLO processes such as the electro-optic effect14,15 and second harmonic generation.3,4

After disclosing an extensive evaluation of the structural, photophysical, and DNA-binding properties exhibited by the trimethylated fluorophore DANPY-1,5 we grew interested in changing substituents at both the naphthylamine and pyridinium units through synthesis. In the discovery phase of our study, 2-amino-6-bromonaphthalene (see 1, Scheme 1) was an ideal starting material because of the convenience of forging two sp3 C–N bonds by routine alkylation.16 However, precursor 1 is expensive, and in substitution events with certain electrophiles, such as those with unprotected hydroxyl groups, reactions were found to produce low yields or no isolable products. As an improvement, we report herein a more practical and versatile approach to DANPY variants made possible by an effort to expand the scope of the Bucherer synthesis of 2-aminonaphthalenes.

Scheme 1. Concise Three-Step Synthesis of Pyrrolidine Dye Variant 4 and Alternative Retrosynthetic Analysis.

Scheme 1

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Results and Discussion

Our primary aim in preparing modified DANPY’s was to increase water solubility and affinity for hydrophilic biomolecules by incorporating hydrogen-bonding functions, such as ether and alcohol groups (entries 6 and 12, Table 1). The addition of groups that allow coating of DNA to yield an alcohol-soluble electro-optic material17,18 is also disclosed. Another pursuit still under development is building amphiphilic dyes suitable for lipid staining (e.g., n-octyl chain, entry 3, Table 1). We have used a theory-aided design process in which properties of dyes with groups of interest were first screened using density functional theory (DFT) calculations in order to predict optimal geometries and both hyperpolarizability (β) and charge-transfer absorbance (λmax) values.

Table 1. Computational Survey of More Hydrophilic (Entries 6–12) or Lipophilic (Entries 2–5) DANPY Variants.

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a

Calculation of λmax performed in Gaussian 09 at CAM-B3LYP/6-31+G(d) theory level.

b

By analytical differentiation.

c

By Marvin/ChemAxon consensus method.

Structures were optimized in chloroform solvent using Gaussian 0919 at the CAM-B3LYP/6-31+G(d) level of theory. Properties were calculated in chloroform at the same level of theory, which has been determined20 to furnish good estimates on the relative β and λmax of chromophores and was effective for predicting the relative optical properties of DANPY-1 and similar dyes.5 Octanol–water partition coefficient (log P) values, a common measure of hydrophobicity, were estimated using the ChemAxon consensus logP method in MarvinSketch.21,22 Data from the computational screen is compiled in Table 1.

Shifting the absorbance maximum or manipulating hyperpolarizability was not a major target of this study; the primary rationale for calculating these properties for derivatives of interest was to evaluate whether optical properties would be comparable to DANPY-1.5 In general, increasing the electron-donating strength of the donor–acceptor compounds of Table 1 is expected to result in a bathochromic shift in the absorbance spectrum and yield dyes with higher hyperpolarizabilities. In most cases, the change in electron-donating power of the naphthylamine moiety23 is minor, resulting in proportionately small effects on λmax and hyperpolarizability. One exception is the deactivated amide carbonyl-containing variant (entry 9), which has a much lower β and bluer absorption maximum. However, changes in side-chain functionalization induce a significant and desirable variation in hydrophobicity, ranging from a log P of 2.66 for entry 3 (similar to that of benzene22) to −1.82 for entry 11 (similar to free leucine). The wide range of logP values suggests that the DANPY nucleus can be tuned for affinity to either hydrophobic or hydrophilic substrates with simple modifications to the naphthylamine substituents.

With modeling data supporting tunable hydrophobicity and little change in hyperpolarizability or λmax across a selection of N-alkyl groups, we set out to test a double SN2 strategy for preparing 2-amino-6-bromonaphthalenes. As illustrated in Scheme 1, 2-pyrrolidino-6-bromo-naphthalene (2) forms in 87% yield upon base-promoted N,N-dialkylation of 1 with 1,4-dichlorobutane [tetrabutylammonium iodide (TBAI) and dimethyl sulfoxide (DMSO), 95 °C] under Finkelstein conditions. Subsequent Suzuki coupling with pyridine 4-boronic acid under the previously optimized5 conditions [1 mol % Pd2(dba)3, 4 mol % SPhos,24 and 4:1 dimethylformamide (DMF)–EtOH,25 90 °C] gives intermediate 2-pyrrolidino-6-pyridyl-naphthalene (3, not shown in Scheme 1) in >60% recrystallized yield on gram scale without chromatography. In a third and final step, site-selective N-methylation in warm acetonitrile gives dye 4 in 76% yield as thin red needles after passage through a plug of silica gel in 10:1 dichloroethane–MeOH and recrystallization from chloroform. Pyrrolidine derivative 4 has been characterized by nuclear magnetic resonance (NMR) and UV/vis spectroscopies in acetone and methanol, respectively. As shown in Figure 2A, there is a 12 nm red shift in its absorbance relative to DANPY-1 and a negligible shift in the wavelength of maximum fluorescence. The small bathochromic shift for 4 aligns with that predicted from DFT calculations and is likely due to the greater electron-donating power of pyrrolidine versus dimethylamine; the reduction of the Stokes shift in a polar methanol environment is likely due to the increased hydrophobicity (larger log P) of the ground state. The photoluminescence quantum yield of 4 at 440 nm in DMSO is 0.053, slightly larger than the 0.045 measured for DANPY-1 using identical protocols4 and consistent with the smaller Stokes shift. Comparable DNA affinity is demonstrated by simple gel electrophoresis separation of a commercial 18 kb DNA ladder (Figure 2B). If 4 is added to a 0.8% agarose gel suspension in a prepour phase (1.0 μg/mL), excellent postrun visualization of the DNA components can be observed by fluorescence at 450 nm excitation with a conventional Bio-Rad GelDoc EZ Imager.

Figure 2.

Figure 2

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UV/visible overlay comparing DANPY-1 and 4 (A) and visualization of oligomeric DNA with 4 (B).

The path of synthesis depicted in Scheme 1 is highly scalable due to the crystalline nature of 2, 3, and 4. However, precursor 1 is expensive ($18/g), and delocalization in its conjugate base lowers its nucleophilicity, giving way to a monomethylated26 byproduct in the parent DANPY-1 synthesis that must be removed by column chromatography. An alternative strategy for installing the dialkyl naphthalene amine in 2 would be to construct its lone sp2 C–N bond by either Pd-catalyzed cross-coupling or formal nucleophilic aromatic substitution. Therefore, other 2,6-difunctionalized naphthalenes were considered for a direct amination (Scheme 1), and one that is advantageous is 6-bromo-2-naphthol (5) because of lower cost ($2/g). As shown in Table 2, we now report that tricycle 2 and five other 6-bromo-2-naphthalene-2-amines (6–10) are readily obtained in a practical manner by simply mixing naphthol 5 with a secondary amine under Bucherer reaction conditions.

Table 2. Direct Amination of 6-Bromo-2-naphthol with Symmetrical Secondary Amines by Bucherer Reaction.

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a

Yield of solid after recrystallization or chromatography.

b

Based on recovered 5 at 25% conv. to 10.

A Bucherer reaction27,28 involves thermal conversion of a naphthol to a naphthylamine, and it has also seen use for transamination events in the 2-aminonaphthalene series. The transformation takes place in aqueous medium in the presence of sulfurous acid or any of its salts (i.e., NaHSO3, Na2SO3, and Na2S2O5). French chemist Robert Lepetit was the first to discover the transformation in 1898.28 Independently, the German chemist Hans Theodor Bucherer recognized its industrial value and was the first to postulate a reversible, equilibrium-based mechanism.29 The process requires temperatures beyond the boiling point of water and is not applicable to benzene substrates because of a temporary disruption in aromaticity. To our knowledge, the scope of the reaction with respect to cyclic amines is underdeveloped, although some isolated examples30−33 of amine condensation with a halogenated (deactivated) naphthol are known. Another report describes aminonaphthalene synthesis by use of microwave irradiation,34 but neutral and electron-rich (methoxylated) naphthol substrates were explored, and only acyclic secondary amines were tested as nucleophiles.

The amination procedure involves magnetic stirring of a mixture of 6-bromo-2-naphthol (5), five equivalents of the desired secondary amine,35 and two equivalents of sodium metabisulfite in water at 150 °C in sealed pressure flasks (Table 2). Na2S2O5 (common name disodium, also called sodium pyrosulfite or sodium disulfite) was chosen as the reagent because once dissolved in water, metabisulfite dianion releases sulfur dioxide as a pungent gas and leaves behind sulfite dianion, the most reactive of sulfurous acid salts known to mediate Bucherer transformation. For all entries in Table 2, the reported yields represent an average of at least two runs conducted on gram scale in which reaction time was restricted to 1 day out of convenience; some combinations of reagents may benefit from prolonged heating. Additionally, in no cases are byproducts visible by thin-layer chromatography (TLC) or 1H NMR analysis. In the event where minor amounts of unreacted 5 are present at workup given the reversible nature of the reaction, a simple flash filtration through a pad of silica gel is sufficient to deliver amine products in analytically pure form36 because naphthol is considerably more polar.

Two other advantages concerning the scope of this methodology are as follows: (1) success in the process is not limited to secondary amines that are water-soluble. As shown in entry 1b, the use of diisobutylamine as nucleophile gives modest levels of conversion in just 24 h even though the reaction mixture remains biphasic. (2) Direct preparation of compound 10 (entry 5) underscores a tolerance of the method to free alcohols. It is probable that an alternative synthetic route to 10 based on iterative N-alkylation would be much longer and require protecting group manipulations.

Based on known literature precedents,27,28 formation of products 2 and 6–10 involves a key bisulfite adduct derived from addition to the keto form of the starting naphthol (see d, Scheme 2). To begin, protonation at C1 commences a typical enol–keto tautomerization, yielding conjugated oxonium cation a. 1,4-Sulfite addition (→c), followed by another tautomerization, is the dominant pathway to tetralone sulfonate d. It is also possible that C3 protonation gives b, with subsequent 1,6-sulfite addition (→c) and enol–keto tautomerization acting as an alternative path to d. In either case, keto forms of 1- and 2-naphthols (a and b) are known28 to behave differently than their nonaromatic counterparts. Cyclic and acyclic alkanones can only furnish 1,2-bisulfite adducts, which are quite useful when conducting purification or isolation.37 Here, 1,2-addition (to either a or b) must be reversible, as the free carbonyl at C2 is required for further transformation to the amine. It is also unlikely that a 1,2-adduct (derived from a) would later converge with d by [2,3]-sigmatropic rearrangement because the tetrahedral intermediate would need to be O– (vs S−) bound.

Scheme 2. Mechanism for Amination is Based on a Rate-Limiting Genesis of Tetralone Sulfonic Acid Adduct d.

Scheme 2

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After rate-determining formation of the tetralone sulfonate (d), the course of product formation is straightforward. Amine condensation with the free carbonyl delivers iminium ion e and then enamine f after proton loss at C1. The final stage involves rearomatization by sodium hydrogen sulfite elimination. With a mechanism established, it becomes clear why overamination of 5 does not occur under these reaction conditions: C–N bond formation is restricted to the hydroxylated position that serves as a latent carbonyl function.

As a salt, the DANPY nucleus is subject to further diversification with respect to its counterion and pyridinium alkyl group. The identity of the anion stems from the choice of electrophile used to build the alkylpyridinium cation, and primary bromides have also proven effective. As shown in Scheme 3, N-alkylation of the pyridine derived from 6(5,36) with bromoalkanes linked to 7-hydroxy coumarin (umbelliferone) give multifunctional fluorophores 12 and 13 as red, amorphous solids.38 A first step in preparing these variants was to secure 1-bromoalkyl ethers of the coumarin (11a,b) by Williamson reaction with the corresponding 1,6- and 1,8-dibromoalkanes. These dye molecules may be suitable for photonic devices that utilize DNA-derived polymer waveguides.39 DANPY-15 was initially developed to be doped into such waveguides as an electro-optic material.6,7,17,18 Prior attempts at such systems required blending the DNA with a dye (such as Disperse Red 1), a cetyltrimethylammonium surfactant, and in many cases a cross-linking agent for thermal stability. As single entities, 12 and 13 are unique in merging a cationic chromophore (that can act as a counterion for DNA) with a cross-linkable coumarin surfactant that undergoes [2 + 2] cycloaddition in the presence of UV light.40 In future work, we hope to show that these molecules will coat the surface of a DNA duplex, solubilize it, offer a reasonable density of chromophores for EO activity, and can be photocross-linked to harden the dye–biopolymer matrix.

Scheme 3. Displacement with Primary Bromides 11a and b Provides Coumarin Dyes 12 and 13.

Scheme 3

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Conclusions

In summary, a short and convergent entry to DANPY dyes has been refined by extending the Bucherer amination of 2-naphthols to cyclic secondary amines. The methodology relies on a less expensive naphthalene precursor relative to earlier work and will facilitate study of structure–function relationships in the donor amine unit of the dye. The synthetic pathway also tolerates modification within the acceptor pyridinium domain, with more elaborate chromophores 12 and 13 now available for DNA-based biophotonics. Additional results will be reported in due course.

Experimental Section

All reactions were carried out in oven- and flame-dried glassware under inert atmosphere in dry degassed solvents using Schlenk and vacuum line techniques. Column chromatography was performed with high-purity Davisil (grade 635) silica gel. TLC was performed with 0.25 mm silica gel 60 F254 plates, and spot visualization was accomplished by exposure to long- and short-wave ultraviolet light. Infrared spectra were recorded on a Fourier transform IR spectrophotometer; peaks are reported in wavenumbers (cm–1) as strong (s), medium (m), weak (w), or broad (br). NMR spectra were recorded on a 500 MHz instrument as part of a user consortium created by California State University Channel Islands (Camarillo, CA). 1H NMR chemical shifts are listed in ppm from tetramethylsilane with the solvent resonance as the internal standard (CDCl3: δ 7.26; (CD3)2CO: δ 2.05; (CD3)2SO: δ 2.50) in the sequence: chemical shift, multiplicity, coupling constants (Hz), and integration. 13C NMR spectra (125 MHz) were recorded (at CSUCI) with proton decoupling; chemical shifts are given to the nearest tenth of a ppm with solvent resonance as the internal standard (CDCl3: δ 77.16; (CD3)2CO: δ 29.84, (CD3)2SO: δ 40.45). High-resolution mass spectra were recorded using electrospray ionization time-of-flight methods at the University of Illinois (Urbana-Champaign). Elemental analyses were conducted at Robertson Microlit Labs (Ledgewood, NJ). UV/visible spectra were recorded in methanol using a spectrophotometer in double-beam mode with a pure solvent reference. Fluorescence spectra were recorded in methanol using a fluorimeter with an excitation wavelength of 450 nm and a grating width of 15 nm for both emission and excitation, subtracting the scattering contribution from a pure methanol reference.

2-Amino-6-bromonaphthalene (1), 6-bromo-2-naphthol (5), potassium carbonate, TBAI, sodium carbonate, tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos), pyridine 4-boronic acid, sodium meta-bisulfite, petroleum ether, hexane, dichloromethane, ethyl acetate, 1,2-dichloroethane, acetic acid, methanol, toluene, heptane, and chloroform were purchased commercially and used as received. DMF and DMSO were passed through a short pad of alumina and vacuum distilled over calcium hydride. Ethanol was distilled over calcium hydride and stored over 3 Å MS. Anhydrous acetonitrile was dispensed from a solvent purification system driven by compressed argon. 1,4-Dichlorobutane was distilled over calcium sulfate. Iodomethane, 1,6-dibromohexane, 1,8-dibromooctane, and all secondary amines were distilled to colorless oils in the absence of a drying agent and used immediately.

1-(6-Bromo-2-naphthyl)pyrrolidine (2) by N,N-Dialkylation Conditions

1,4-Dichlorobutane (1.63 mL, 14.9 mmol, 3.0 equiv) was added to a suspension of TBAI (11.0 g, 29.8 mmol, 6.0 equiv) and potassium carbonate (1.37 g, 9.94 mmol, 2.0 equiv) in DMSO (30 mL, 0.125 M). The mixture was submerged in an oil bath heated to 95 °C, stirring was continued, and 2-amino-6-bromo-naphthalene (1, 1.10 g, 4.47 mmol, 1.0 equiv) was added slowly by a syringe pump as a solution in 10 mL of DMSO at a rate of 0.1 mL per minute. After 20 h of stirring at 95 °C, the mixture was diluted with ethyl acetate (40 mL) and water (40 mL) and moved to a separatory funnel. The organic layer was removed and the aqueous layer was washed twice with ethyl acetate (20 mL). The combined organic layers were washed three times with saturated sodium chloride to remove residual water and DMSO. The resulting solution was dried over MgSO4, filtered, and concentrated by rotary evaporation. During this step, iridescent brown salt crystals were observed to precipitate out of solution. This substance proved to be TBAI and, if desired, could be removed with an additional filtration step. It is not necessary, however, because the salt does not migrate through the silica gel used for purification. Concentration afforded a shiny, light brown solid. Column chromatography in 30:1 hexane:ethyl acetate (TLC Rf = 0.47) provided 1.08 g (3.91 mmol, 87%) of a pale yellow solid that can be recrystallized from hot ethanol. Melting point = 168–169 °C. IR (KBr pellet): 2967 (m), 2840 (m), 1627 (s), 1591 (s), 1509 (s), 1458 (w), 1397 (s), 1173 (br, w), 1062 (w), 936 (m), 841 (s), 806 (s). 1H NMR (500 MHz, CDCl3): δ 7.81 (s, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.39 (dd, J = 8.8, 2.0 Hz, 1H), 6.99 (dd, J = 8.8, 2.0 Hz, 1H), 6.70 (s, 1H), 3.39 (t, J = 6.5 Hz, 4H), 2.06 (t, J = 6.5 Hz, 4H). 13C NMR (125 MHz, CDCl3): δ 146.2, 133.9, 129.6, 129.4, 128.1, 127.6, 127.4, 116.6, 114.2, 104.6, 47.9, 25.6. HRMS calcd for C14H14BrN, 276.0388; found, 276.0391. Anal. Calcd for C14H14BrN: C, 60.89; H, 5.11; N, 5.07. Found: C, 60.69; H, 4.91; N, 4.59.

4-(6-(Pyrrolidin-1-yl)naphthalene-2-yl)pyridine (3)

A heavy-walled glass pressure vessel equipped with a magnetic stir bar and a threaded Teflon/O-ring seal was charged with 1-(6-bromo-2-naphthyl)pyrrolidine (2, 1.03 g, 3.73 mmol), pyridine 4-boronic acid (688 mg, 5.60 mmol, 1.5 equiv), tris(dibenzylideneacetone)dipalladium(0) (51.1 mg, 0.0558 mmol, 0.015 equiv), SPhos (91.6 mg, 0.223 mmol, 0.06 equiv), and sodium carbonate (789 mg, 7.44 mmol, 2.0 equiv). The vessel was fitted with a rubber septum and a vent needle, evacuated, and purged with argon on the Schlenk line. Anhydrous DMF (60 mL) and ethanol (15 mL) were introduced by a syringe under a positive pressure of argon (4:1 DMF–EtOH, 0.05 M). Some solid reaction contents dissolved, but homogeneity was not achieved at 23 °C; a turbid light green suspension was observed. After removing the septum and sealing the reactor, the mixture was stirred vigorously for 4 h at 85 °C (oil bath). At this point, the reaction mixture was less turbid and a Pd black precipitate was visible. A routine TLC analysis confirmed the absence of the starting bromoarene (2). The mixture was cooled to room temperature, transferred to a separatory funnel, and diluted with water (75 mL) and ethyl acetate (75 mL). After removing the organic layer, the aqueous layer was washed two times with 50 mL of ethyl acetate, and the combined organic layers were washed three times with an equal volume of saturated sodium chloride in order to remove residual DMF. The purified extract was dried over MgSO4, filtered through a medium porosity glass frit, and concentrated by rotary evaporation to give an orange solid residue. The crude material can be purified by recrystallization from hot toluene. In the event, ∼1.5 g of the solid residue dissolved readily in 40–45 mL of boiling toluene but required a hot filtration to remove traces of insoluble deposits. Slow cooling of the hot filtrate delivered the product as light orange, flaky nodules and clusters. After leaving the flask at −20 °C overnight, crystals of 3 were isolated in >60% yield as a single crop by filtration, washing with small portions of cold petroleum ether, and drying under high vacuum. Alternatively, the crude material is absorbed onto silica gel and filtered through a short column in 1:1:1 petroleum ether:ethyl acetate:dichloromethane (the latter additive prevents “streaking” of the diamine, TLC Rf = 0.35). Rotary evaporation of the long-wave UV-active fractions results in spontaneous deposition of light orange crystals that were vacuum-filtered, washed with cold petroleum ether, and dried under high vacuum (0.98 g, 96% yield). Either mode of purification serves to remove uncharacterized nonpolar impurities (Rf > 0.5) and 4,4′-bipyridine (Rf = 0.15) derived from the homocoupling of pyridine 4-boronic acid. Melting point = 221–222 °C. IR (KBr pellet): 2976 (w), 2857 (w), 1655 (w), 1624 (s), 1591 (s), 1543 (w), 1505 (m), 1485 (m), 1458 (w), 1406 (m), 1362 (w), 1219 (m), 1177 (w), 993 (w), 828 (s), 802 (w). 1H NMR (500 MHz, CDCl3): δ 8.63 (d, J = 5.9 Hz, 2H), 8.00 (s, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 6.4 Hz, 2H), 7.64 (dd, J = 8.8, 2.0 Hz, 1H), 7.04 (dd, J = 8.8, 2.0 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 3.44 (t, J = 6.6 Hz, 4H), 2.08 (t, J = 6.6 Hz, 4H). 13C NMR (125 MHz, CDCl3): δ 149.9, 148.9, 146.9, 135.9, 129.8, 129.6, 126.9, 126.7, 126.1, 124.7, 121.5, 116.6, 104.3, 47.9, 25.7. HRMS calcd for C19H19N2+ (M + 1), 275.1543; found, 275.1549. Anal. Calcd for C19H18N2: C, 83.18; H, 6.61; N, 10.21. Found: C, 82.07; H, 6.51; N, 9.98.

1-Methyl-4-(6-(pyrrolidin-1-yl)naphthalen-2-yl)pyridinium Iodide (4)

In a dry glass vial containing a magnetic stir bar and a Teflon-lined screw cap, 140.0 mg of 4-(6-(pyrrolidin-1-yl)naphthalene-2-yl)pyridine (3, 0.510 mmol) was dissolved in 5.1 mL of acetonitrile (0.10 M) under argon. To the resulting light orange solution, iodomethane (48.0 μL, 0.771 mmol, 1.5 equiv) was added by a microsyringe. The vial was capped and submerged in an oil bath heated to 60 °C. After 10 min, the reaction mixture was more orange in color and gentle solvent reflux had begun. Upon 24 h of stirring at this temperature, a bright red solution and dark precipitate were observed. The solid is the pyridinium iodide, which can be recovered by microfiltration but in variable purity because of a potential for dimethylation to give a dicationic material. Typically, the mixture was cooled to room temperature and homogenized using a minimal volume of commercial chloroform (which contains 1–2% ethanol). Glacial acetic acid (32 μL, 1.1 equiv) was also added to ensure an acidic pH and promote dissolution. The solution was then saturated with silica gel, dry-packed onto the absorbent, and passed through a broad but short plug of silica (3 cm wide x 3 cm long) with 88:9:3 dichloroethane:methanol:acetic acid as an eluant (TLC Rf = 0.30). An uncharacterized yellow-orange fraction elutes just before the desired product, which is bright red in solution and light blue to violet under long-wave UV irradiation. The column also removes a dicationic impurity, as the dimethylamine unit can also quaternize by methylation. Pooling and rinsing of pure fractions with chloroform, followed by concentration on a rotovap connected to a high vacuum, gave a dark red, tacky residue. Prolonged exposure to high vacuum may be required to remove the less volatile acetic acid. The solid was then recrystallized from a boiling mixture of chloroform (25 mL) and methanol (2–4 mL, just enough to promote dissolution) using a hot filtration step to remove any insoluble material. Upon slow cooling to 23 °C and further chilling to −20 °C overnight, the dye deposited as thin, bright red needles that were collected on a fine porosity glass frit, washed twice with petroleum ether, and dried under high vacuum. By this method, 161 mg (76% yield) of product 4 was recovered in a single crop. Melting point = 260 °C (decomposition). IR (KBr): 3034 (w), 2918 (m), 2851 (w), 1641 (m), 1607 (s), 1560 (w), 1524 (s), 1503 (m), 1478 (m), 1406 (w), 1385 (m), 1370 (w), 1227 (m), 1198 (m), 825 (m), 750 (s), 660 (m). 1H NMR (500 MHz, (CD3)2CO): δ 9.04 (d, J = 7.0 Hz, 2H), 8.60 (s, 1H), 8.58 (d, J = 7.0 Hz, 2H), 7.98 (dd, J = 8.8, 2.0 Hz, 1H), 7.92 (d, J = 9.0 Hz, 1H), 7.82 (d, J = 9.0 Hz, 1H), 7.17 (dd, J = 9.0, 2.5 Hz, 1H), 6.87 (d, J = 2.5 Hz, 1H), 4.56 (s, 3H), 3.48 (t, J = 4.5 Hz, 4H), 2.08 (t, J = 4.5 Hz, 4H). 13C NMR (125 MHz, (CD3)2SO): δ 153.9, 146.9, 143.1, 136.2, 130.0, 128.5, 126.1, 124.5, 124.0, 123.5, 122.1, 116.3, 103.1, 54.3, 46.8, 24.3. HRMS Calcd for C20H21N2+, 289.1705; found, 289.1706. Anal. Calcd for C20H21IN2: C, 57.70; H, 5.08; N, 6.73. Found: C, 50.29; H, 5.12; N, 5.66.

6-Bromo-N,N-dimethylnaphthalene-2-amine (6) by Representative Bucherer Conditions

A heavy glass-walled “Chemglass” pressure reactor equipped with a threaded Teflon/O-ring closure and a magnetic stir bar was charged directly with 4.09 g of 6-bromo-2-naphthol (5, 18.3 mmol) and 6.96 g (36.6 mmol, 2.0 equiv) of sodium metabisulfite as solids. Water (18 mL, 1.0 M) was then added, dissolving the base but not the starting material. Up to 5.0 equiv35 of secondary amine (in this case, 16.5 mL of a 25% solution of dimethylamine in water, 91.5 mmol) was added by a syringe and the resulting cloudy suspension was stirred vigorously for 24 h in an oil bath heated to 150 °C. Melting of the substrate leads to partial dissolution, and the heterogeneous mixture gradually turns dark brown in color. After cooling to room temperature and venting the flask, the reaction mixture was extracted three times with 50 mL portions of ethyl acetate. The combined organic layers were washed once with an equal volume of saturated sodium bicarbonate and sodium chloride and dried over MgSO4. Filtration to remove the drying agent and concentration by rotary evaporation gave a light yellow residue that can be passed through a pad of silica gel in 10:1 hexane:Et2O (to remove any trace of 5 present by TLC analysis) or directly recrystallized from hexane to give a flaky, free-flowing white solid (4.21 g, 92% yield). Melting point = 122–124 °C. IR (KBr pellet): 2884 (m), 1625 (s), 1589 (s), 1559 (w), 1505 (s), 1382 (s), 1236 (m), 1181 (m), 1159 (m), 1060 (m), 937 (m), 877 (m), 844 (s), 807 (s). 1H NMR (500 MHz, CDCl3): δ 7.83 (s, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.42 (dd, J = 8.8, 1.5 Hz, 1H), 7.17 (dd, J = 9.3, 2.2 Hz, 1H), 6.87 (d, J = 1.5 Hz, 1H), 3.05 (s, 6H). 13C NMR (125 MHz, CDCl3): δ 149.7, 148.9, 133.6, 129.5, 127.97, 127.94, 127.9, 117.2, 115.2, 106.2, 40.8. HRMS calcd for C12H13BrN+ (M + 1), 250.0231; found, 250.0233. Anal. Calcd for C12H12BrN: C, 57.62; H, 4.84. Found: C, 57.72; H, 4.61.

6-Bromo-N,N-diisobutylnaphthalen-2-amine (7)

The representative Bucherer amination procedure described above was performed on a 1.00 g scale (4.50 mmol of 6-bromo-2-naphthol 5) with 1.71 g (8.99 mmol, 2.0 equiv) of sodium metabisulfite, 4.5 mL of water (1.0 M), and 3.93 mL (22.5 mmol, 5.0 equiv) of diisobutylamine. Melting point = 70–72 °C. IR (KBr): 3389 (m), 2955 (s), 2865 (s), 2842 (m), 1626 (s), 1587 (s), 1466 (m), 1308 (m), 1220 (m), 1170 (m), 893 (w), 860 (m), 805 (m). 1H NMR (500 MHz, CDCl3): δ 7.80 (s, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.41 (dd, J = 8.8, 2.0 Hz, 1H), 6.90 (dd, J = 8.8, 2.0 Hz, 1H), 6.76 (s, 1H), 3.03 (d, J = 6.9 Hz, 4H), 1.97 (septet, J = 6.4 Hz, 2H), 1.04 (d, J = 6.4 Hz, 12H). 13C NMR (125 MHz, CDCl3): δ 146.3, 133.9, 129.7, 129.6, 128.6, 128.1, 127.7, 119.0, 115.0, 104.3, 52.0, 28.0, 20.7. HRMS calcd for C18H25BrN+ (M + 1), 334.1170; found, 334.1166. Anal. Calcd for C15H16BrN: C, 64.67; H, 7.24; N, 4.19. Found: C, 60.59; H, 5.78; N, 5.00.

1-(6-Bromo-2-naphthyl)pyrrolidine (2) by Bucherer Reaction

The representative Bucherer amination procedure described above was performed on a 1.00 g scale (4.50 mmol of 6-bromo-2-naphthol 5) with 1.71 g (8.99 mmol, 2.0 equiv) of sodium metabisulfite, 4.5 mL of water (1.0 M), and 1.88 mL (22.5 mmol, 5.0 equiv) of pyrrolidine. The product was recovered in 81% yield and was identical in every respect (mp, TLC, IR, 1H NMR, and 13C NMR analysis) to that obtained by the N,N-dialkylation procedure.

1-(6-Bromonaphthalen-2-yl)piperidine (8)

The representative Bucherer amination procedure described above was performed on a 1.01 g scale (4.54 mmol of 6-bromo-2-naphthol 5) with 1.72 g (9.05 mmol, 2.0 equiv) of sodium metabisulfite, 4.5 mL of water (1.0 M), and 2.22 mL (22.5 mmol, 5.0 equiv) of piperidine. Melting point = 139–140 °C. IR (KBr): 2961 (s), 2929 (s), 2874 (s), 2861 (s), 1746 (s), 1627 (m), 1462 (m), 1373 (m), 1300 (w), 1240 (s), 1112 (m), 1049 (s), 752 (w). 1H NMR (500 MHz, CDCl3): δ 7.85 (d, J = 1.5 Hz, 1H), 7.61 (d, J = 9.3 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.44 (dd, J = 8.3, 2.0 Hz, 1H), 7.30 (dd, J = 8.8, 2.4 Hz, 1H), 7.10 (s, 1H), 3.26 (t, J = 5.4 Hz, 4H), 1.77 (m, 4H), 1.63 (quintet, J = 5.4 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 143.5, 136.1, 133.0, 129.8, 129.6, 128.8, 128.2, 127.1, 120.6, 119.2, 52.3, 25.3, 23.9. HRMS calcd for C15H17BrN+ (M + 1), 289.0544; found, 289.0530. Anal. Calcd for C15H16BrN: C, 62.08; H, 5.56; N, 4.83. Found: C, 62.01; H, 5.46; N, 4.84.

4-(6-Bromonaphthalen-2-yl)morpholine (9)

The representative Bucherer amination procedure described above was performed on a 1.01 g scale (4.54 mmol of 6-bromo-2-naphthol 5) with 1.72 g (9.05 mmol, 2.0 equiv) of sodium metabisulfite, 4.5 mL of water (1.0 M), and 1.94 mL (22.5 mmol, 5.0 equiv) of morpholine. Melting point = 152–153 °C. IR (KBr): 3019 (s), 2968 (w), 2927 (w), 2860 (w), 1733 (s), 1593 (m), 1374 (m), 1250 (m), 1217 (s), 1123 (m), 1047 (m), 907 (s), 752 (s), 667 (s), 652 (s). 1H NMR (500 MHz, CDCl3): δ 7.87 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.47 (dd, J = 8.8, 2.0 Hz, 1H), 7.27 (dd, J = 9.3, 2.4 Hz, 1H), 7.10 (br s, 1H), 3.92 (t, J = 4.9 Hz, 4H), 3.27 (t, J = 4.9 Hz, 4H). 13C NMR (125 MHz, CDCl3): δ 140.5, 133.1, 129.9, 129.8, 129.6, 128.6, 128.1, 119.8, 117.1, 110.1, 66.9, 49.8. HRMS calcd for C14H15BrNO+ (M + 1), 291.0337; found, 291.0334. Anal. Calcd for C14H14BrNO: C, 57.55; H, 4.83; N, 4.79. Found C, 57.55; H, 4.81; N, 4.84.

(1-(6-Bromonaphthalen-2-yl)piperidin-4-yl)methanol (10)

The representative Bucherer amination procedure described above was performed on a 1.01 g scale (4.51 mmol of 6-bromo-2-naphthol 5) with 1.72 g (9.03 mmol, 2.0 equiv) of sodium metabisulfite, 5.0 mL of water (1.0 M), and 2.59 mL (22.5 mmol, 5.0 equiv) of 4-piperidine methanol. In this case, 1H NMR analysis of the workup extract showed only 25% conversion to product. A more polar 1:1 cyclohexane:Et2O eluant was used to separate (Rf difference = 0.35) and isolate both 10 (289 mg, 20% yield) and the recovered starting material (626 mg, 2.81 mmol). Melting point = 166–168 °C. IR (KBr): 3306 (br), 2996 (w), 2941 (m), 2822 (m), 1626 (m), 1588 (m), 1558 (w), 1498 (m), 1445 (w), 1388 (s), 1347 (w), 1315 (w), 1269 (w), 1254 (m), 1223 (w), 1191 (s), 1093 (m), 1029 (s), 931 (m), 881 (w), 854 (s), 801 (m), 661 (w). 1H NMR (500 MHz, CDCl3): δ 7.86 (d, J = 1.5 Hz, 1H), 7.63 (d, J = 9.3 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.45 (dd, J = 8.3, 2.0 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.17 (br s, 1H), 3.83 (d, J = 12.7 Hz, 2H), 3.58 (d, J = 6.4 Hz, 2H), 2.84 (t, J = 11.7 Hz, 2H), 1.91 (d, J = 12.7 Hz, 2H), 1.77–1.68 (m, 1H). 13C NMR (125 MHz, CDCl3): δ 150.0, 133.3, 129.52, 129.51, 129.4, 128.4, 127.8, 121.0, 116.6, 110.2, 67.9, 49.8, 38.7, 28.7. HRMS calcd for C16H19BrNO+ (M + 1), 320.0650; found, 320.0652. Anal. Calcd for C16H18BrNO: C, 60.01; H, 5.67; N, 4.37. Found C, 59.88; H, 5.50; N, 4.42.

7-(6-Bromohexyloxy)-2H-chromen-2-one (11a)

7-Hydroxycoumarin (umbelliferone) can be recrystallized from ethanol (if desired) as light yellow, flaky nodules. A 50 mL round-bottom flask equipped with a magnetic stir bar was charged with umbelliferone (1.50 g, 9.25 mmol), potassium carbonate (3.84 g, 27.8 mmol, 3.0 equiv), and dry acetone (18.5 mL, 0.5 M). These solids partially dissolved, forming a light yellow suspension that was treated with 1,6-dibromohexane (11.0 mL, 71.5 mmol, 7.7 equiv) using a syringe. A large excess of electrophile is used in order to discourage dietherification by the phenoxide anion. After 48 h of stirring at 23 °C, TLC analysis of the reaction mixture revealed only trace amounts of the remaining starting material. Thus, a stream of nitrogen was used to purge out over half of the solvent volume, and the mixture was partitioned between 50 mL of water and 50 mL of 1:1 ethyl acetate:hexanes in a separatory funnel. The organic layer was collected and the bright yellow aqueous layer was washed twice with 30 mL of 1:1 ethyl acetate:hexanes. The pooled organic layers were dried over MgSO4 and concentrated. Purification by silica gel chromatography with 2.5:1 petroleum ether:ethyl acetate as an eluant (Rf = 0.35) delivered 1.876 g (62% yield) of product as an off-white solid. Melting point = 58–60 °C. IR (KBr pellet): 2943 (s), 2863 (w), 1733 (s), 1720 (s), 1707 (s), 1624 (s), 1616 (s), 1559 (m), 1541 (m), 1509 (s), 1398 (m), 1292 (s), 1236 (s), 1142 (s), 1133 (s). 1H NMR (500 MHz, CDCl3): δ 7.63 (d, J = 9.3 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.83 (dd, J = 8.3, 2.4 Hz, 1H), 6.80 (d, J = 2.4 Hz, 1H), 6.25 (d, J = 9.3 Hz, 1H), 4.02 (t, J = 6.4, 2H), 3.43 (t, J = 6.8 Hz, 2H), 1.91 (quintet, J = 6.8 Hz, 2H), 1.84 (quintet, J = 6.8 Hz, 2H), 1.55–1.48 (m, 4H). 13C NMR (500 MHz, CDCl3): δ 162.5, 161.4, 146.6, 143.6, 128.9, 113.15, 113.12, 112.6, 101.5, 68.5, 33.9, 32.7, 29.0, 28.0, 25.4. HRMS calcd for C15H18BrO3+ (M + 1), 325.0439; found, 325.0437. Anal. Calcd for C15H17BrO3: C, 55.40; H, 5.27. Found: C, 55.61; H, 5.20.

7-(6-Bromooctyloxy)-2H-chromen-2-one (11b)

The procedure given directly above for the (bromohexyloxy)chromenone 11a was repeated on a scale involving 1.50 g of umbelliferone (9.25 mmol), 3.84 g of potassium carbonate (27.8 mmol, 3.0 equiv), and 14.0 mL of 1,8-dibromooctane (76.0 mmol, 8.2 equiv) in 18.5 mL of acetone (0.5 M). An identical workup and purification gave 1.762 g (54% yield) of an off-white solid. Melting point = 67–69 °C. IR (KBr pellet): 2934 (s), 2853 (m), 1733 (s), 1719 (s), 1706 (s), 1622 (s), 1559 (m), 1541 (m), 1508 (m), 1398 (w), 1291 (m), 1236 (m), 1142 (m), 1130 (m). 1H NMR (500 MHz, CDCl3): δ 7.63 (d, J = 9.8 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.83 (dd, J = 8.8, 2.4 Hz, 1H), 6.80 (d, J = 2.4 Hz, 1H), 6.24 (d, J = 9.3 Hz, 1H), 4.01 (t, J = 6.4, 2H), 3.41 (t, J = 6.8 Hz, 2H), 1.86 (quintet, J = 6.8 Hz, 2H), 1.81 (quintet, J = 6.4 Hz, 2H), 1.54–1.41 (m, 4H), 1.41–1.32 (m, 4H). 13C NMR (500 MHz, CDCl3): δ 162.5, 161.5, 156.1, 143.6, 128.8, 113.15, 113.08, 112.5, 101.4, 68.7, 34.1, 32.9, 29.3, 29.1, 28.8, 28.2, 26.0. HRMS calcd for C17H22BrO3+ (M + 1), 353.0752; found, 353.0750. Anal. Calcd for C17H21BrO3: C, 57.80; H, 5.99. Found: C, 58.10; H, 6.15.

4-(6-Dimethylamino)naphthalene-2-yl)-1-(8-(2-oxo-2H-chromen-7-yloxy)hexyl) Pyridinium Bromide (12)

A flame-dried 25 mL round-bottom flask with a magnetic stir bar was charged with 153 mg (0.470 mmol, 1.0 equiv) of 7-(6-bromohexyloxy)-2H-chromen-2-one (11a) and 117 mg (0.471 mmol, 1.0 equiv) of N,N-dimethyl-6-(pyridine-4-yl)-naphthalene-2-amine5 as solids. After evacuating and back-filling the flask with argon on a vacuum line, its contents were dissolved in 4.7 mL of acetonitrile (0.10 M). The flask was equipped with a water condenser and submerged in an oil bath heated to 75 °C. After 30 min of stirring, the initial light yellow solution had given way to an orange solution and a gentle reflux of solvent had begun. Upon 40 h of stirring at reflux, the reaction mixture was bright red. The mixture was cooled to 23 °C and homogenized with ∼1.0 mL of chloroform (containing 1–2% ethanol). The solution was then saturated with silica gel, dry-packed onto the absorbent, and passed through a broad but short plug of silica gel (3 cm wide × 3 cm long) with 88:9:3 dichloromethane:methanol:acetic acid as an eluant (Rf = 0.50). Concentration of the dark red, long-wave UV-active fractions, first on a rotovap and then under high vacuum, gave 250 mg (93%) of 12 as a crusty, bright red solid. Melting point = 90–95 °C. IR (KBr pellet): 3418 (br), 2937 (m), 1728 (m), 1710 (m), 1615 (s), 1557 (w), 1521 (m), 1506 (m), 1383 (m), 1280 (w), 1231 (m), 1172 (m), 1125 (m), 1030 (w), 839 (m), 753 (m), 638 (w). 1H NMR (500 MHz, (CD3)2CO): δ 9.14 (d, J = 7.3 Hz, 2H), 8.57 (d, J = 7.3 Hz, 2H), 8.56 (s, 1H), 7.96 (dd, J = 8.8, 2.0 Hz, 1H), 7.92 (d, J = 9.3 Hz, 1H), 7.85 (d, J = 9.8 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.32 (dd, J = 9.3, 2.4 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.89 (dd, J = 8.8, 2.4 Hz, 1H), 6.83 (d, J = 2.0 Hz, 1H), 6.18 (d, J = 9.3 Hz, 1H), 4.81 (t, J = 7.3 Hz, 2H), 4.11 (t, J = 6.4 Hz, 2H), 3.14 (s, 6H), 2.22–2.16 (m, 2H), 1.87–1.82 (m, 2H), 1.64–1.54 (m, 4H). HRMS calcd for C32H33N2O3+, 493.2491; found, 493.2475. Anal. Calcd for C32H33BrN2O3: C, 67.01; H, 5.80. Found: C, 61.85; H, 6.00.

4-(6-Dimethylamino)naphthalene-2-yl)-1-(8-(2-oxo-2H-chromen-7-yloxy)octyl) Pyridinium Bromide (13)

The procedure for compound 12 described above was followed on a scale involving 230 mg (0.651 mmol, 1.0 equiv) of 7-(6-bromooctyloxy)-2H-chromen-2-one (11b) and 161 mg (0.648 mmol, 1.0 equiv) of N,N-dimethyl-6-(pyridine-4-yl)-naphthalene-2-amine.5 A matching approach to workup, purification, and recovery provided 350 mg (90% yield) of 13 as a red solid residue. Melting point = 130–134 °C. IR (KBr pellet): 3418 (br), 2935 (m), 1727 (m), 1709 (m), 1614 (s), 1557 (w), 1522 (m), 1507 (m), 1470 (w), 1383 (w), 1280 (w), 1231 (m), 1174 (m), 1124 (m), 1031 (w), 840 (m), 756 (m), 638 (w). 1H NMR (500 MHz, (CD3)2CO): δ 9.09 (d, J = 6.8 Hz, 2H), 8.57 (d, J = 7.3 Hz, 2H), 8.55 (d, J = 2.0 Hz, 1H), 7.96 (dd, J = 8.8, 2.0 Hz, 1H), 7.91 (d, J = 9.3 Hz, 1H), 7.87 (d, J = 9.3 Hz, 1H), 7.84 (dd, J = 8.8, 4.9 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.32 (dd, J = 9.3, 2.5 Hz, 1H), 7.01 (d, J = 2.5 Hz, 1H), 6.88 (dd, J = 8.8, 2.4 Hz, 1H), 6.83 (d, J = 2.0 Hz, 1H), 6.19 (d, J = 9.3 Hz, 1H), 4.76 (t, J = 7.3 Hz, 2H), 4.09 (t, J = 6.4 Hz, 2H), 3.12 (s, 6H), 2.18–2.10 (m, 2H), 1.82–1.76 (m, 2H), 1.52–1.38 (m, 8H). HRMS calcd for C34H37N2O3+, 521.2804; found, 521.2785. Anal. Calcd for C34H37BrN2O3: C, 67.88; H, 6.20. Found: C, 65.78; H, 6.39.

Acknowledgments

Generous financial support was provided by California Lutheran University and the NSF Center on Materials and Devices for Information Technology Research (CMDITR, no. DMR 0120967). Work at UW was additionally supported by Air Force Research Laboratory (FA8659-06-D-5401) and the Air Force Office of Scientific Research (FA9550-15-1–0319). H.E.Z. was an NSF REU Awardee in the 2014 Hooked on Photonics program (no. CHE 0851730). CLU’s Chemistry Department benefits from an Amgen- and NSF-sponsored consortium of user access to a 500 MHz NMR lab at California State University, Channel Islands (VIA-CI, CCLI 0737081). The authors also thank Prof. Bruce Robinson, Dr. Meghana Rawal (UW), and undergraduates Yoojin Jang and Hasmik Adetyan (CLU) for helpful discussion and experimental assistance. Calculations were conducted using the University of Washington Department of Chemistry Stuart cluster, which is supported by the UW Student Technology Fund.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.9b03107.

  • Copies of 1H and 13C NMR spectra for all numbered compounds (PDF)

Author Present Address

§ The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037.

Author Present Address

∥ Department of Chemistry, University of Pennsylvania, 231 S 34 St., Philadelphia, PA 19104.

Author Present Address

⊥ Division of Biological Sciences, U.C. San Diego, 9500 Gilman Dr., La Jolla, CA 92093.

The authors declare no competing financial interest.

Supplementary Material

ao9b03107_si_001.pdf (1MB, pdf)

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