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. Author manuscript; available in PMC: 2022 Sep 28.
Published in final edited form as: New J Chem. 2021 Aug 17;45(36):16833–16840. doi: 10.1039/d1nj03030b

Efficient Synthesis of 6,6´-Diamido-2,2´-dipicolylamine Ligands for Potential Phosphate Anion Sensing

Shuai Wang a,b, Lichong Gong c, Georges El Fakhri a, Junfeng Wang a
PMCID: PMC8865135  NIHMSID: NIHMS1735697  PMID: 35221667

Abstract

We report here the efficient synthesis of 6,6´-diamido-2,2´-dipicolylamines (DA-DPAs) which could be applied to phosphate anion sensing via pre-formed metal complexes. The design was based on the retrosynthetic analysis. This strategy enabled us to achieve the functionalized DA-DPAs in satisfactory yields with high purity using the Boekelheide rearrangement. Meanwhile, all the intermediates could be easily purified by silica gel column chromatography.

Graphical Abstract

graphic file with name nihms-1735697-f0001.jpg

Through retrosynthetic analysis, functionalized 6,6´-diamido-2,2´-dipicolylamines (DA-DPAs) have been efficiently synthesized, which may accelerate the development of selective probes towards phosphate anions.

Introduction

Biologically relevant anions play fundamental roles in a wide range of biochemical processes, [1, 2] but the design of probes for sensing of these anions is much more challenging than that for sensing cations. Inorganic pyrophosphate (PPi) - the byproduct of adenosine triphosphate (ATP) hydrolysis - plays an important role in many biological processes. PPi participates in enzymatic reactions, such as deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) polymerization and cyclic adenosine monophosphate (AMP) synthesis, which are catalyzed by DNA polymerase and adenylate cyclase respectively.[1–10] Moreover, abnormal levels of PPi are known to be associated with various diseases, such as arthritis, cancer, crystal deposition disease, Paget’s disease, and vascular calcification.[11, 12] Furthermore, detection of PPi release has been successfully applied to Real-Time DNA Sequencing by an enzymatic luminometric inorganic pyrophosphate (PPi) detection assay.[13] Direct sensing of PPi via a small molecular chemical probe would therefore be helpful in the early diagnosis of relevant diseases. A challenge in the design of PPi sensors is the inherently high concentration of ATP and phosphate anions in biological samples, both of which are structurally similar to PPi. A suitable sensor for PPi would therefore require both strong binding affinity and great selectivity towards PPi over other anions. The strong hydration effects of PPi and the presence of multiple oxygen atoms in the anion that can serve as potential coordination sites make PPi a particularly challenging substrate for responsive sensing probes.[14]

Numerous efforts have been devoted to the sensing of phosphate anions,[15–38] and one of the most successful strategies is based on properly positioned binuclear zinc complexes. As shown in chart 1, 1·Zn2 with meta-positioned DPA-Zn chelating groups has been applied to the sensing of PPi, ATP, guanosine 3′-diphosphate-5′-di(tri)phosphate ((p)ppGpp), flavin adenosine dinucleotide (FAD), and phosphorylated proteins.[39–42] The phenoxide bridged ligands 2·Zn2 bear more rigid structures and have been successfully used for PPi chelation. 2a·Zn2 was the first successful selective probe to bind PPi in buffered aqueous media, and demonstrated both strong binding affinity toward PPi (3.4 nM) and good selectivity over ATP (40.2 times stronger PPi binding than ATP).[16] 2a·Zn2 was able to detect low nM concentration of PPi in HEPES buffer in the presence of a large amount of ATP (50 – 250 fold excess). Ligand 2b·Zn2 with four additional acetamide groups further reinforced the binding strength towards PPi (20 pM),[20] while, ligands 2c·Zn2 and 2d·Zn2, bearing smaller hydrogen bond donors, showed much lower binding affinity towards PPi (0.55 and 0.17 μM).[43] This lower binding affinity is likely due to the effect of repulsive interactions between negative charges of the guest anion (PPi) and the lone pair electrons of the nitrogen atom.

Chart 1.

Chart 1

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Representative phosphate anion chelators based on binuclear zinc complexes

The current work builds on our ongoing interest in pyrophosphate sensing[30, 44, 45] and the hypothesis that steric hindrance of the bulky R’ group may result in a higher degree of selectivity towards PPi while maintaining the strong binding affinity towards PPi, as demonstrated by Hong et al recently.[37] Hence, efficient synthesis of DA-DPA ligands would advance the effort towards selective pyrophosphate anion sensing, but derivatization of these ligands has been limited. The synthesis of DA-DPA ligands that are highly polar nature remains challenging and many efforts have been reported to result in failure.[46–49]

In most literature reports, DA-DPA ligands such as 6a were synthesized using direct bromination of the picolyl methyl group. However, this reaction usually suffers from low yields with multiple by-products (Scheme 1),[50–62] making the purification quite difficult. Picolinates could be an alternative in the functionalization [63, 64] and oxidation the methyl group in 3 to carboxylic acid VII requires the protection of the amino group to avoid its oxidation,[65] meanwhile, the oxidation of the methyl group takes place smoothly with low to moderate yields (26–62%).[65–67]

Scheme 1.

Scheme 1.

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Traditional synthesis of chelating group 6a.

We aim to develop a synthetic route to DA-DPA ligands applicable to a broad substrate scope with high yields and easy purification starting with the commercially available 2-amino-6-methylpyridine 3 building on our previous experience.[68] Retrosynthetic analysis to develop our strategy was carried out as shown in Scheme 2, in which we planned to use high yielding Boekelheide rearrangement for the clean conversion.[69] The protecting group R3 is used to avoid the high polarity and allow for normal phase purification. Protecting group R2 was also introduced to avoid diacetylation of the amino group under high reaction temperature (reflux). Simultaneous deprotection of R2 and R3 is highly desirable and would afford 6 in one step. We therefore chose p-methoxybenzyl (PMB) as a protecting group which is stable under basic and slight acid conditions. Here we report our results of efficient synthesis of ligands 6.

Scheme 2.

Scheme 2.

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Retrosynthetic strategy for the synthesis of 6.

Results and discussion

As shown in Scheme 3, commercially available 2-amino-6-methylpyridine 3 readily reacted with 4-anisaldehyde, followed by NaBH4 reduction to give 7 in 93% yield. Subsequent oxidation with meta-chloroperoxybenzoic acid (m-CPBA) gave pyridine N-oxide 8 in 98% yield. Purification was easily achieved by trapping 8 on a short pad of silica gel column and eluted with EtOAc and MeOH. Notably, oxidation of 4 (R1 = Me) by m-CPBA gave a mixture of unidentified byproducts. Next, we envisioned that both amide formation and Boekelheide rearrangement might be accomplished by one suitable reagent (Shown in Table S1). As expected, the reaction of 8 with acetic anhydride was quite successful, resulting in 9a in a 96% yield.[68] However, carrying out this acylation by reflux of 8 in acyl chloride resulted in a poor yield of 9a (20%). Considering the high reactivity of acyl chloride, this poor yield may be due to the low boiling point of acyl chlorides (51 °C). We overcame this by heating the reaction mixture to 140 °C in a sealed tube, and the reaction of acetyl chloride with compound 8 also gave 9a in a comparable yield (89%). Similarly, the reaction of benzoyl chloride with 8 at 140 °C also gave a satisfactory yield of 9b (95%), but the reaction did not proceed at 40 °C. The lack of reactivity at low temperature indicates that the Boekelheide rearrangement may require harsher reaction condition (high temperature). Notably, although Boekelheide rearrangement was reported to take place under mild conditions by using trifluoroacetic anhydride[70], the reaction of 8 with trifluoroacetic anhydride was very complicated, giving a mixture of products with no trace of the target compound 9c and we are not disclosing the details here.

Scheme 3.

Scheme 3.

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The synthetic route of 9.

Synthesis of the target compounds 6a and 6b was then carried out using the key intermediates 9a and 9b (Scheme 4). Saponification of 9a and 9b resulted in a clean, quantitative conversion to 10a and 10b followed by a similarly high yielding, clean bromination to give 11a and 11b in 95% yields, respectively. PMB-NH2 was selected to react with the key bromide intermediates 11a and 11b in acetonitrile, as the deprotection of all PMB groups can be accomplished in one step to afford the final ligands 6a and 6b. Due to the high polarity of the final ligands, high purity and clean deprotection of 12a and 12b would be very crucial during the synthesis. To our delight, the bromides 11a and 11b reacted with PMB-NH2 smoothly to afford the key intermediates 12a and 12b in high yields, and easily purified by silica gel chromatography with EtOAc/Hexanes system. Deprotection of PMB by TFA gave exclusively the final ligands 6a and 6b, which made their separation from the other reagent easily accomplished using a short pad of silica gel.

Scheme 4.

Scheme 4.

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The synthetic route of 6a and 6b.

We next selected dodecanoic acid to test the applicability of the strategy on a wide range of substrates. We chose this long chain hydrophobic acid because acids are generally more commercially available than acyl chlorides and anhydrides and because the hydrophobic pocket formed by the long flexible chain may provide anion selectivity. We chose to activate the acid with pentafluorophenol because pentafluorophenol esters are easily made and are reactive but bench stable and because the group provides a UV handle by which substrates can be detected. As shown in Scheme 5, when the reaction of 13 with 8 was carried out at 140 °C, we observed that only one dodecanoyl group was introduced, which indicated that the activated ester might not be sufficiently active for Boekelheide rearrangement (Depicted in Figure S1). This was followed by the addition of another portion of acetic anhydride in this reaction mixture, and intermediate 9d was separated in 66% yield via a one-pot reaction. Target compound 6d was then easily synthesized through the similar high-yielding hydrolysis (→10d), bromination (→11d), alkylation (→12d), and global deprotection (→6d) sequence.

Scheme 5.

Scheme 5.

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The synthetic route of ligand 6d.

Experimental

General methods

All reagents and starting materials were obtained from commercial sources, including Sigma-Aldrich (St. Louis, MO), Thermo Fisher Scientific, Oakwood Products, Inc, and were used as received. Reactions were monitored by TLC using a UV lamp that emits at 254 nm. When necessary, the reactions were also checked by an Agilent 1200 series HPLC system coupled with a multiwavelength UV detector and a model 6310 ion trap mass spectrometer (Santa Clara, CA) equipped with a Luna C18 column (Phenomenex, 100 × 2mm, 5 μm, 100 Å) (LC-MS). HPLC was carried out by using a 7 min gradient method (LC-Method 1): the mobile phase A was water with 0.1% Formic acid (FA) added; mobile phase B was MeCN with 0.1% FA added; gradient: 5% B to 95% B from 0 to 3 min, 95% B from 3 to 4.5 min, 95% to 5% B from 4.5 to 5 min, 5% B from 5 to 7 min; flow rate at 0.7 mL/min. The silica gel used in flash column chromatography was from Aldrich (Cat. 60737, pore size 60 Å, 230–400 mesh). The products were characterized by 1H NMR and 13C NMR using a Jeol 500MHz spectrometer. NMR samples were dissolved in chloroform-d3 (CDCl3), methanol-d4 (CD3OD) or DMSO‑d6 containing tetramethylsilane as a reference standard. Chemical shifts were expressed as ppm and calculated downfield from the NMR signal of a reference standard. J-coupling was expressed as Hz, and its splitting patterns were reported as s, d, t, q, or m. Unless otherwise specified, the purities of all new compounds were over 95 % determined by HPLC.

The synthesis of reactive ester (pentafluorophenyl n-dodecanoate) Pentafluorophenyl n-dodecanoate 13 was synthesized according to the previously reported method.[71]

1H NMR (500 MHz, CDCl3) δ 2.65 (t, J = 7.4 Hz, 2H), 1.76 (m, 2H), 1.47 – 1.17 (m, 16H), 0.87 (t, J = 6.9 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 169.71, 33.44, 31.99, 29.66, 29.64, 29.47, 29.41, 29.22, 28.94, 24.85, 22.77, 14.19.

N-(4-methoxybenzyl)-6-methylpyridin-2-amine (7)

To the solution of 2-amino-6-methylpyridine (2.16 g, 20 mmol) in 50 mL ethanol was added 4-anisaldehyde (3 g, 22 mmol), which was stirred under reflux at 80 °C for 5 h. NaBH4 (1.13 g, 30 mmol) was then added to the solution slowly which continued to heat at 80 °C until the intermediate product was consumed. The mixture was purified by column chromatography to generate compound 7 as white crystalline solid (4.22 g, 93%). 1H NMR (500 MHz, CDCl3) δ 7.31 (t, J = 7.8 Hz, 1H), 7.27 (d, J = 8.7 Hz, 2H), 6.91 – 6.82 (m, 2H), 6.45 (d, J = 7.3 Hz, 1H), 6.17 (d, J = 8.3 Hz, 1H), 4.94 (s, 1H), 4.37 (d, J = 5.7 Hz, 2H), 3.78 (s, 3H), 2.37 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 158.92, 158.30, 156.82, 138.23, 131.11, 128.72, 114.08, 112.56, 103.05, 55.37, 46.16, 24.26. LC-MS (LC-MS Method 1, ESI): tR = 5.86 min, m/z: [M+H] Calcd for C14H17N2O 229.1; Found 229.7.

2-((4-Methoxybenzyl)amino)-6-methylpyridine 1-oxide (8)

Compound 7 (2.28 g, 10 mmol) was dissolved in 10 mL CH2Cl2, followed by addition of mCPBA (2.46 g, 12 mmol), and stirred at room temperature (RT) for 30 min. Upon completion (monitored by TLC), the solvent was evaporated under vacuum. The obtained crude product was then purified by column chromatography eluted with EtOAC:MeOH (10:1, v/v) to give pyridine N-oxide intermediates 8 as a yellow solid (2.39 g, 98%). 1H NMR (500 MHz, DMSO-d6) δ 7.67 (t, J = 6.6 Hz, 1H), 7.29 – 7.17 (m, 2H), 6.98 (t, J = 8.0 Hz, 1H), 6.86 – 6.81 (m, 2H), 6.58 (dd, J = 7.7, 1.7 Hz, 1H), 6.51 (dd, J = 8.5, 1.8 Hz, 1H), 4.36 (d, J = 6.6 Hz, 2H), 3.67 (s, 3H), 2.30 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 158.88, 44150.45, 146.43, 131.15, 128.90, 126.28, 114.38, 112.40, 103.90, 55.55, 44.78, 18.31. LC-MS (LC-MS Method 1, ESI): tR = 3.08 min, m/z: [2M+H] Calcd for C28H33N4O4 489.2; Found 489.7.

The synthetic methods for compounds 9a-b and 9d

Compound 8 (456.6 mg, 2 mmol) was dissolved in 2 mL acetic anhydride or benzoyl chloride, which was heated to 140 °C for 4 h or 8 h, respectively. Upon completion, the mixture was concentrated under reduced pressure, and was then purified by column chromatography to provide liquid compound 9a (630.4 mg, 96%) or 9b (855.6 mg, 95%).

Compound 9a: 1H NMR (500 MHz, CDCl3) δ 7.65 (t, J = 7.8 Hz, 1H), 7.18 (s, 1H), 7.15 – 7.11 (m, 2H), 6.99 (s, 1H), 6.82 – 6.71 (m, 2H), 5.17 (s, 2H), 5.02 (s, 2H), 3.75 (s, 3H), 2.14 (s, 3H), 2.07 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 170.63, 158.85, 155.69, 154.84, 138.80, 129.78, 129.37, 120.63, 119.56, 113.88, 66.26, 55.30, 50.60, 23.47, 20.96. LC-MS (LC-MS Method 1, ESI): tR = 3.47 min, m/z: [M+H]+ Calcd for C18H21N2O4 329.1; Found 329.7.

Compound 9b: 1H NMR (500 MHz, CDCl3) δ 8.15 – 8.05 (m, 2H), 7.64 – 7.54 (m, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.39 – 7.28 (m, 3H), 7.32 – 7.23 (m, 3H), 7.19 (t, J = 7.6 Hz, 2H), 7.10 (d, J = 7.6 Hz, 1H), 6.75 – 6.70 (m, 1H), 6.49 (d, J = 8.0 Hz, 2H), 5.43 (s, 2H), 5.27 (s, 2H), 3.72 (d, J = 0.7 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 170.81, 166.22, 158.81, 155.48, 155.38, 137.97, 136.11, 133.42, 130.39, 129.98, 129.96, 129.88, 128.83, 128.61, 128.13, 121.58, 118.39, 113.76, 66.62, 55.25, 51.00. LC-MS (LC-MS Method 1, ESI): tR = 4.36 min, m/z: [M+H]+ Calcd for C28H25N2O4 453.1; Found 453.7.

Compound 8 (456.6 mg, 2.0 mmol) was combined with compound 13 (1.46 g, 4 mmol) without solvent and was then stirred at 140 °C overnight. The reaction mixture was cooled down to RT and acetic anhydride (2 mL) was then added to the mixture, which was heated to 140 °C for another 4 h. The mixture was purified by column chromatography to give compound 9d as a white solid (621.1 mg, 66%).

Compound 9d: 1H NMR (500 MHz, CDCl3) δ 7.64 (t, J = 7.8 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.15 – 7.09 (m, 2H), 6.96 (s, 1H), 6.84 – 6.72 (m, 2H), 5.17 (s, 2H), 5.00 (s, 2H), 3.75 (s, 3H), 2.23 (t, J = 7.6 Hz, 2H), 2.15 (s, 2H), 1.60 (t, J = 7.3 Hz, 2H), 1.30 – 1.12 (m, 16H), 0.86 (t, J = 7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 173.36, 170.63, 158.80, 155.78, 154.87, 138.69, 130.01, 129.44, 120.94, 119.58, 113.84, 66.34, 55.29, 50.57, 35.15, 31.99, 29.69, 29.55, 29.46, 29.42, 29.38, 25.51, 22.77, 20.97, 14.21. LC-MS (LC-MS Method 1, ESI): tR = 5.39 min, m/z: [M+H]+ Calcd for C28H41N2O4 469.3; Found 469.7.

General synthetic method for compounds 10a-b and 10d

Compounds 9a or 9b (1.5 mmol) were dissolved in 10 mL THF, and KOH (2.25 mmol) dissolved in 2 mL water was added to the reaction solution, which was stirred at RT for 2 h. The crude product was then purified by column chromatography to provide compound 10a as a white solid (422.5 mg, 98%) or 10b (507.1 mg, 97%).

Compound 10a: 1H NMR (500 MHz, CDCl3) δ 7.65 (m, 1H), 7.12 (d, J = 8.3 Hz, 4H), 6.78 (d, J = 8.3 Hz, 2H), 5.02 (s, 2H), 4.73 (s, 2H), 3.75 (d, J = 1.2 Hz, 3H), 2.06 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 170.63, 158.90, 155.69, 150.84, 138.89, 129.70, 129.27, 120.24, 118.63, 113.94, 63.90, 55.31, 50.73, 23.40. LC-MS (LC-MS Method 1, ESI): tR = 3.03 min, m/z: [M+H]+ Calcd for C16H19N2O3 287.1; Found 287.7.

Compound 10b: 1H NMR (500 MHz, CDCl3) δ 7.35 (m, 3H), 7.32 – 7.25 (m, 3H), 7.21 (dd, J = 8.3, 7.0 Hz, 2H), 6.91 (d, J = 7.6 Hz, 1H), 6.82 – 6.75 (m, 2H), 6.54 (d, J = 8.0 Hz, 1H), 5.27 (s, 2H), 4.66 (s, 2H), 3.75 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 170.93, 158.90, 158.39, 155.09, 138.24, 136.21, 130.44, 129.90, 129.56, 128.65, 128.21, 120.44, 117.38, 113.93, 63.76, 55.29, 51.12. LC-MS (LC-MS Method 1, ESI): tR = 3.48 min, m/z: [M+H]+ Calcd for C21H21N2O3 349.1; Found 349.7.

Compound 9d (468.6 mg, 1.0 mmol) was dissolved in 10 mL THF, and KOH (84 mg, 1.5 mmol) dissolved in 2 mL water was added to the reaction solution, which was stirred at 80 °C for 5 h. Upon completion, the solvent was evaporated by vacuum and the resultant residue purified by column chromatography, resulting in compound 10d as a colorless oil (395.1 mg, 93%).

Compound 10d: 1H NMR (500 MHz, CDCl3) δ 7.63 (t, J = 7.7 Hz, 1H), 7.12 (m, 3H), 6.96 – 6.88 (m, 1H), 6.81 – 6.69 (m, 2H), 4.98 (s, 2H), 4.72 (s, 2H), 3.74 (d, J = 0.9 Hz, 3H), 2.21 (t, J = 7.5 Hz, 2H), 1.60 (t, J = 7.3 Hz, 2H), 1.33 – 1.08 (m, 16H), 0.85 (t, J = 7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 173.36, 159.31, 158.85, 154.38, 138.78, 129.91, 129.37, 120.54, 118.67, 113.88, 64.01, 63.96, 55.33, 55.29, 55.24, 50.70, 35.07, 31.99, 29.69, 29.54, 29.45, 29.41, 29.35, 25.54, 22.77, 14.21. LC-MS (LC-MS Method 1, ESI): tR = 4.97 min, m/z: [M+H]+ Calcd for C26H40N2O3 427.2; Found 427.7.

General synthetic method for compounds 11a-b and 11d

Compound 10 (1 mmol) reacted with PBr3 (325.2 mg, 1.2 mmol) in 10 mL DCM at RT for 1 h. The resulting mixture was dissolved in DCM, washed with saturated sodium bicarbonate and brine, dried over MgSO4, and filtered. The solution was concentrated under reduced pressure to produce compounds 11a (331.1 mg, 95%), 11b (391.2 mg, 95%) or 11d (445.1 mg, 91%) in white solids.

Compound 11a: 1H NMR (500 MHz, CDCl3) δ 7.63 (t, J = 7.8 Hz, 1H), 7.33 – 7.23 (m, 1H), 7.17 – 6.87 (m, 3H), 6.79 – 6.70 (m, 2H), 5.03 (s, 2H), 4.48 (s, 2H), 3.74 (s, 3H), 2.09 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 170.58, 158.88, 156.44, 154.91, 139.07, 129.71, 129.42, 121.36, 120.72, 113.91, 55.30, 50.55, 33.27, 23.56. LC-MS (LC-MS Method 1, ESI): tR = 3.71 min, m/z: [M+H]+ Calcd for C16H18BrN2O2 349.0; Found 349.7.

Compound 11b: 1H NMR (500 MHz, CDCl3) δ 7.36 – 7.32 (m, 2H), 7.30 – 7.26 (m, 4H), 7.19 (m, 2H), 7.08 (d, J = 7.5 Hz, 1H), 6.79 – 6.74 (m, 2H), 6.44 (d, J = 8.0 Hz, 1H), 5.28 (s, 2H), 4.47 (s, 2H), 3.74 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 170.71, 158.87, 156.10, 155.55, 138.20, 136.05, 130.40, 130.13, 129.91, 128.86, 128.17, 121.86, 120.30, 113.78, 55.27, 50.97, 33.35. LC-MS (LC-MS Method 1, ESI): tR = 4.16 min, m/z: [M+H]+ Calcd for C21H20BrN2O2 411.0; Found 411.7.

Compound 11d: 1H NMR (500 MHz, CDCl3) δ 7.61 (t, J = 7.8 Hz, 1H), 7.26 (s, 1H), 7.15 – 7.09 (m, 2H), 6.94 (s, 1H), 6.78 – 6.72 (m, 2H), 5.00 (s, 2H), 4.47 (s, 2H), 3.73 (s, 3H), 2.26 (t, J = 7.6 Hz, 2H), 1.61 (t, J = 7.4 Hz, 2H), 1.31 – 1.10 (m, 16H), 0.85 (t, J = 6.9 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 173.43, 158.83, 156.54, 154.94, 139.02, 129.91, 129.49, 128.87, 121.40, 121.01, 114.09, 113.87, 55.27, 50.53, 35.25, 33.34, 31.99, 29.69, 29.55, 29.45, 29.42, 29.38, 25.54, 22.77, 14.22. LC-MS (LC-MS Method 1, ESI): tR = 5.76 min, m/z: [M+H]+ Calcd for C26H39BrN2O2 489.2; Found 489.7.

General synthetic method for compounds 12a-b and 12d

To a solution of compound 11 (0.5 mmol) was added 4-methoxybenzylamine (34.3 mg, 0.25 mmol), potassium carbonate (68.9 mg, 0.5 mmol) and potassium iodide (16.5 mg, 0.1 mmol), and the mixture was stirred at 80 °C for 5 h. Upon completion of the reaction, the crude product was purified by column chromatography to produce white solid compounds 12a (152.5 mg, 91%), 12b (184.2 mg, 92%) or 12d (166.2 mg, 70%).

Compound 12a: 1H NMR (500 MHz, CDCl3) δ 7.69 (t, J = 8.0 Hz, 2H), 7.41 (s, 2H), 7.25 (s, 4H), 7.05 (d, J = 8.0 Hz, 4H), 6.80 (d, J = 8.0 Hz, 2H), 6.68 (d, J = 8.1 Hz, 4H), 5.08 (s, 4H), 4.20 (d, J = 23.6 Hz, 6H), 3.78 (s, 3H), 3.63 (s, 6H), 2.09 (s, 6H). 13C NMR (126 MHz, CDCl3) δ 170.91, 161.95, 161.66, 160.75, 158.93, 154.73, 150.38, 139.45, 132.69, 129.31, 128.73, 123.24, 121.54, 121.17, 114.54, 56.67, 55.40, 55.22, 55.01, 50.69, 23.61. LC-MS (LC-MS Method 1, ESI): tR = 3.11 min, m/z: [M+H]+ Calcd for C40H44N5O5 674.3; Found 674.7.

Compound 12b: 1H NMR (500 MHz, CDCl3) δ 7.35 – 7.26 (m, 7H), 7.24 – 7.15 (m, 5H), 7.14 – 7.06 (m, 6H), 6.86 – 6.82 (m, 2H), 6.73 (m, 4H), 6.47 (d, J = 7.8 Hz, 2H), 5.26 (s, 4H), 3.79 (d, J = 1.2 Hz, 3H), 3.69 (d, J = 1.2 Hz, 6H), 3.61 (s, 4H), 3.44 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 170.79, 159.47, 158.87, 158.80, 155.09, 137.61, 136.38, 130.91, 130.17, 130.10, 130.00, 129.83, 128.75, 128.00, 120.68, 120.33, 113.77, 59.11, 57.47, 55.36, 55.27, 55.23, 55.19, 51.12. LC-MS (LC-MS Method 1, ESI): tR = 3.51 min, m/z: [M+H]+ Calcd for C50H48N5O5 798.3; Found 798.7.

Compound 12d: 1H NMR (500 MHz, CDCl3) δ 7.58 (t, J = 7.7 Hz, 2H), 7.36 (d, J = 7.6 Hz, 2H), 7.24 (s, 3H), 7.10 (d, J = 8.2 Hz, 4H), 6.82 (d, J = 8.1 Hz, 3H), 6.71 (d, J = 8.2 Hz, 4H), 4.99 (s, 4H), 3.77 (s, 3H), 3.70 (d, J = 6.6 Hz, 10H), 3.55 (s, 2H), 2.21 (t, J = 7.7 Hz, 4H), 1.59 (t, J = 7.3 Hz, 4H), 1.30 – 1.09 (m, 32H), 0.85 (t, J = 6.9 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 173.29, 159.93, 158.89, 158.75, 154.48, 138.32, 130.73, 130.09, 130.06, 129.48, 121.21, 120.21, 113.78, 59.29, 57.69, 55.32, 55.22, 50.63, 35.12, 32.00, 29.69, 29.55, 29.49, 29.42, 25.54, 22.77, 22.74, 14.22. LC-MS (LC-MS Method 1, ESI): tR = 6.20 min, m/z: [M+H]+ Calcd for C60H85N5O5 954.6; Found 954.7.

General synthetic method for compounds 6a-b and 6d

Compound 12 (0.2 mmol) was dissolved in trifluoroacetic acid (2 mL) and refluxed for 6–8 h. Upon reaction completion, the solvent was evaporated under vacuum. The resulting mixture was dissolved in EtOAc and water, basified with sodium carbonate to the neutral pH. The aqueous layer was extracted with EtOAc three times and washed with saturated NaCl solution, and concentrated under vacuum. The crude product was further purified by column chromatography eluting with EtOAC:MeOH (10:1, v/v) together with 0.5% triethylamine to give the corresponding ligands 6a (58.2 mg, 93%), 6b (80.5 mg, 92%) or 6d (106.5 mg, 90%) as white solids.

Compound 6a: 1H NMR (500 MHz, Methanol-d4) δ 7.99 (d, J = 7.9 Hz, 2H), 7.77 (m, 2H), 7.13 (m, 2H), 4.25 (t, J = 3.8 Hz, 3H), 2.19 – 2.12 (m, 6cH). 13C NMR (126 MHz, Methanol-d4) δ 170.67, 151.77, 139.20, 118.34, 113.39, 50.93, 22.75. LC-MS (LC-MS Method 1, ESI): tR = 2.27 min, m/z: [M+H]+ Calcd for C16H20N5O2 314.1; Found 314.7. mp 190–192 °C.

Compound 6b: 1H NMR (500 MHz, CDCl3) δ 8.89 (s, 2H), 8.23 (d, J = 8.3 Hz, 2H), 7.97 – 7.87 (m, 4H), 7.67 (t, J = 7.9 Hz, 2H), 7.56 – 7.50 (m, 2H), 7.44 (dd, J = 8.4, 7.0 Hz, 4H), 7.00 (d, J = 7.4 Hz, 2H), 3.89 (s, 4H). 13C NMR (126 MHz, CDCl3) δ 165.81, 151.41, 139.11, 134.27, 132.30, 128.85, 127.40, 127.33, 118.37, 112.66, 53.78. LC-MS (LC-MS Method 1, ESI): tR = 2.90 min, m/z: [M+H]+ Calcd for C26H24N5O2 438.1; Found 438.7. mp 165–167 °C.

Compound 6d: 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 8.3 Hz, 1H), 7.60 (t, J = 7.9 Hz, 2H), 6.92 (d, J = 7.4 Hz, 2H), 3.90 (s, 4H), 2.37 (t, J = 7.5 Hz, 4H), 1.68 (p, J = 7.5 Hz, 4H), 1.42 – 1.14 (m, 32H), 0.85 (t, J = 6.8 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 172.36, 151.53, 139.16, 117.80, 112.81, 52.90, 37.73, 31.99, 29.72, 29.60, 29.53, 29.43, 29.39, 25.46, 22.77, 14.21. LC-MS (LC-MS Method 1, ESI): tR = 4.20 min, m/z: [M+H]+ Calcd for C36H60N5O2 594.4; Found 594.7.

Conclusions

In sum, 6,6´-diamido-2,2´-dipicolylamines (DA-DPAs) are a class of promising ligands for the development of high-affinity phosphate anions in buffered aqueous media. We carried out a retrosynthetic analysis and we adopted our recent functionalization of 2-methyl pyridines via Boekelheide rearrangement in this strategy. Installation of the PMB protecting groups allowed the avoidance of high polarity intermediates and the simultaneous deprotection of all the protecting groups at the final step makes the synthesis very efficient. Additionally, all intermediates and final ligands are easily purified by silica gel column chromatography without prep-HPLC purification. This strategy enabled easy access to a variety of DA-DPA ligands and we anticipate that this work will accelerate the development of selective probes towards phosphate anions.

Supplementary Material

ESI

Acknowledgements

The studies were supported by the NIH grants K25AG061282 and S10OD025234.

Footnotes

Conflicts of interest

There are no conflicts to declare.

Notes and references

‡ Footnotes relating to the main text should appear here. These might include comments relevant not central to the matter under discussion, limited experimental and spectral data, and crystallographic data.

Electronic Supplementary Information (ESI) available: [details of any supplementary information available should be included here]. See DOI: 10.1039/d1nj03030b

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