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Synlett 2018; 29(16): 2176-2180
DOI: 10.1055/s-0037-1610233
cluster
© Georg Thieme Verlag Stuttgart · New York

Configurationally Stable Atropisomeric Acridinium Fluorophores

Christian Fischer
Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland   eMail: christof.sparr@unibas.ch
,
Christof Sparr  *
Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland   eMail: christof.sparr@unibas.ch
› InstitutsangabenWe gratefully acknowledge the Swiss National Science Foundation (BSSGI0-155902/1), the University of Basel, and the NCCR Molecular Systems Engineering for generous financial support.
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Publikationsverlauf

Received: 15. Juni 2018

Accepted after revision: 13. Juli 2018

Publikationsdatum:
03. August 2018 (online)

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In Memoriam Kurt Mislow.

Published as part of the Cluster Atropisomerism

Abstract

Arylated heterocyclic fluorophores are particularly useful scaffolds for numerous applications, such as bioimaging or synthetic photochemistry. While variation of the substitution pattern at the heterocycle and aryl groups allows dye modulation, the bond rotational barriers are also strongly affected. Unsymmetrically substituted ring systems of rotationally restricted arylated heterocycles therefore lead to configurationally stable atropisomeric fluorophores. Herein, we describe these characteristics by determining the properties and configurational stability of atropisomeric, tri-ortho-substituted naphthyl-acridinium fluorophores. A significant barrier to rotation of >120 kJ mol–1 was measured, which renders these dyes and related compounds distinct ­atropisomers with stereoisomer-specific properties over a broad temperature range.

Key words

atropisomerism - heterocycles - fluorophores - acridinium salts - barrier to rotation
 

  • References and Notes

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  • 9 General Procedure for the Double Directed ortho-MetalationTo a solution of bis(3-methoxyphenyl)-amine (160 μmol) in n-hexane (2.0 mL) was added a solution of n-butyllithium in hexanes (176 μL, 1.49 mol L–1, 320 μmol) at RT. The mixture was stirred 6 h at 65 °C. The reaction mixture was directly used in the next step.
  • 10 General Procedure for the Transformation of Esters into Acridinium SaltsTo the reaction mixture of the metalated aryl aniline in n-hexane (160 μmol) at –20 °C was added a solution of carboxylic acid ester (100 μmol) in anhydrous THF (0.60 mL), and the reaction mixture was allowed to warm to RT over 12 h. Aqueous HBr (1.00 mL, 48%) was added, followed by water (20 mL), and the mixture was extracted by CHCl3/i-PrOH (4 × 10 mL; 85:15). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Column chromatography using 100% CH2Cl2 to CH2Cl2/MeOH (100:2 to 100:3 to 100:4) provided the product.
  • 11 (±)-3-(Dimethylamino)-1,8-dimethoxy-9-(naphthalen-1-yl)-10-phenylacridinium bromide salt (4a)Prepared according to the above general procedures using 5-methoxy-N 1-(3-methoxyphenyl)-N 3,N 3-dimethyl-N-phenylbenzene-1,3-diamine (55.8 mg, 160 μmol) and methyl 1-naphthoate (18.6 mg, 100 μmol). Purification provided a brown-red solid (14.4 mg, 26%, HPLC purity: 89% at 400 nm, decomp. at 131 °C): Rf  = 0.12 (CH2Cl2/MeOH, 10:1); IR (neat): νmax = 3369w, 2925w, 2361w, 1623s, 1598s, 1497s, 1475s, 1427m, 1377m, 1349s, 1255s, 1168w, 1102s, 972m, 785s, 768s, 707m. 1H NMR (500 MHz, CDCl3): δ = 7.95 (1 H, d, 3 J = 8.2 Hz, C5′H), 7.87–7.91 (3 H, m, C4′H, C3′′H, C5′′H), 7.79–7.81 (1 H, m, C4′′H), 7.60 (1 H, t, 3 J = 8.4 Hz, C6H), 7.46–7.52 (4 H, m, C3′H, C6′H, C2′′H, C6′′H ), 7.41–7.42 (1 H, m, C8′H), 7.34–7.37 (1 H, m, C7′H), 7.09 (1 H, d, 3J = 6.9 Hz, C2′H), 6.64 (1 H, d, 3J = 8.0 Hz, C7H), 6.57 (1 H, d, 3 J = 8.8 Hz, C5H), 6.32 (1 H, d, 4J = 1.2 Hz, C2H), 5.48 (1 H, d, 4J = 1.3 Hz, C4H), 3.14 (3 H, s, C1OCH3), 3.12 (6 H, br, N(CH3)2), 2.99 (3 H, s, C8OCH3). 13C NMR (125 MHz, CDCl3): δ = 161.1 (C1), 159.8 (C8), 157.3 (C3), 155.1 (C9), 145.3 (C4a), 142.0 (C10a), 140.0 (C1′), 138.7 (C1′′), 136.4 (C6), 132.2 (C4′a), 132.2 (C3′′), 132.1 (C8′a), 132.0 (C5′′), 131.1 (C4′′), 128.1 (C5′), 128.1 (C2′′), 128.0 (C6′′), 127.0 (C4′), 126.0 (C7′), 125.6 (C6′), 125.1 (C8′), 124.9 (C3′), 121.9 (C2′), 116.4 (C9a), 115.3 (C8a), 109.7 (C5), 106.0 (C7), 95.9 (C2), 89.1 (C4), 56.8 (C1OCH3), 56.2 (C8OCH3), 41.2 (N(CH3)2). ESI-MS: m/z calcd for C33H29N2O2 +: 485.2224; found: 485.2226 [M+]. Luminescence spectroscopy (in MeCN): λabs1: 504 nm; λabs2: 431 nm; λabs3: 311 nm; εabs1: 8.5·103 L cm mol–1; εabs2: 1.6·104 L cm mol–1; εabs3: 4.1·104 L cm mol–1; λem(exc 495 nm): 590 nm; Stokes shift: 86 nm; E0,0: 2.22 eV. Cyclic voltammetry (in MeCN, vs. SCE): E1/2(P*/P–): +1.36 V; E1/2(P/P–): –0.86 V.
  • 12 (±)-3-(Dimethylamino)-9-(4-fluoronaphthalen-1-yl)-1,8-dimethoxy-10-phenylacridinium bromide salt (4b)Prepared according to the above general procedures using 5-methoxy-N 1-(3-methoxyphenyl)-N 3,N 3-dimethyl-N-phenylbenzene-1,3-diamine (55.8 mg, 160 μmol) and methyl 4-fluoro-1-naphthoate (20.4 mg, 100 μmol). Purification gave a brown red solid (20.1 mg, 34%, HPLC purity: 93% at 400 nm, decomp. at 134 °C): Rf  = 0.14 (CH2Cl2/MeOH, 10:1). IR (neat): νmax = 2934w, 1623s, 1598s, 1503s, 1469s, 1429m, 1348m, 1256s, 1233m, 1166w, 1098s, 1036w, 907w, 767s, 707m. 1H NMR (500 MHz, CDCl3): δ = 8.22 (1 H, d, 3 J = 8.8 Hz, C5′H), 7.87–7.91 (2 H, m, C3′′H, C5′′H), 7.78–7.81 (1 H, m, C4′′H), 7.55–7.61 (2 H, m, C6′H, C6H), 7.46–7.52 (2 H, m, C2′′H, C6′′H), 7.43–7.44 (2 H, m, C7′H, C8′H), 7.17–7.21 (1 H, m, C3′H), 7.01–7.04 (1 H, m, C2′H), 6.64 (1 H, d, 3 J = 7.9 Hz , C7H), 6.57 (1 H, d, 3 J = 8.8 Hz, C5H), 6.36 (1 H, d, 4 J = 1.2 Hz, C2H), 5.48 (1 H, d, 4 J = 1.2 Hz, C4H), 3.20 (3 H, s, C1OCH3), 3.12 (6 H, br, N(CH3)2), 3.04 (3 H, s, C8OCH3). 13C NMR (125 MHz, CDCl3): δ = 160.9 (C1), 159.6 (C8), 158.0 (d, 2 JCF = 251 Hz, C4′), 157.3 (C3), 154.0 (C9), 145.3 (C4a), 142.1 (C10a), 138.7 (C1′′), 136.3 (C6), 135.9 (d, 4 JCF = 4.8 Hz, C1′), 133.5 (d, 3 JCF = 4.7 Hz, C8′a), 132.2 (C3′′), 132.0 (C5′′), 131.1 (C4′′), 128.1 (C2′′), 128.0 (C6′′), 127.1 (C7′), 126.0 (C6′), 125.2 (d, 4 JCF = 2.6 Hz, C8′), 122.6 (d, 2 JCF = 17.0 Hz, C4′a), 121.6 (d, 3 JCF = 8.2 Hz, C2′), 120.6 (d, 3 JCF = 5.1 Hz, C5′), 116.8 (C9a), 115.3 (C8a), 109.8 (C5), 108.5 (d, 2 JCF = 20.4 Hz, C3′), 105.9 (C7), 96.2 (C2), 89.2 (C4), 56.9 (C8OCH3), 56.2 (C1OCH3), 41.0 (N(CH3)2). 19F NMR (471 MHz, CDCl3): δ = –124.6. ESI-MS: m/z calcd for C33H28FN2O2 +: 503.2128; found: 503.2129 [M+]. Luminescence spectroscopy (in MeCN): λabs1: 501 nm; λabs2: 430 nm; λabs3: 311 nm; εabs1: 5.9·103 L cm mol–1; εabs2: 1.0·104 L cm mol–1; εabs3: 2.9·104 L cm mol–1; λem(exc 496 nm): 591 nm; Stokes shift: 90 nm; E0,0: 2.22 eV. Cyclic voltammetry (in MeCN, vs. SCE): E1/2(P*/P–): +1.37 V; E1/2(P/P–): –0.85 V.
  • 13 General Procedure for the Preparation of the leuco-Form A solution of dye 4a or 4b in EtOH (10.0 μmol, ca. 0.01 mol L–1) was treated with a suspension of sodium borohydride in EtOH (ca. 0.2 mol L–1) until the intense red color faded. The solution was concentrated in vacuo, extracted with Et2O (3 x 10 mL) and washed with water (20 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give the leuco-form 5a and 5b, respectively: Guin J. Besnard C. Lacour J. Org. Lett. 2010; 8: 1748
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  • 14 1,8-Dimethoxy-N,N-dimethyl-9-(naphthalen-1-yl)-10-phenyl-9,10-dihydroacridin-3-amine (5a)Prepared according to the above general procedure.Rf  = 0.62 (CH2Cl2100%). IR (neat): νmax = 3361w, 3194w, 2922s, 2853m, 1632w, 1592m, 1468m, 1258m, 1090m, 1021m, 909w, 798s, 733m, 700m. 1H NMR (600 MHz, CDCl3): δ = 8.98 (1 H, d, 3 J = 8.7 Hz, C8′H), 7.75 (1 H, d, 3 J = 8.0 Hz, C5′H), 7.69 (1 H, dd, 3 J = 7.3 Hz, 4 J = 0.7 Hz, C2′H), 7.63–7.66 (2 H, m, C3′′H, C5′′H), 7.55–7.58 (2 H, m, C4′H, C7′H), 7.48–7.52 (3 H, m, C2′′H, C4′′H, C6′′H), 7.41–7.44 (1 H, m, C6′H), 7.27–7.30 (1 H, m, C3′H), 6.82–6.85 (1 H, m, C6H), 6.61 (1 H, s, C9H), 6.25 (1 H, d, 3 J = 8.0 Hz, C7H), 5.92 (1 H, d, 3 J = 8.4 Hz, C5H), 5.74 (1 H, d, 4 J = 2.2 Hz, C2H), 5.28 (1 H, d, 4 J = 2.2 Hz, C4H), 3.43 (3 H, s, C8OCH3), 3.43 (3 H, s, C1OCH3), 2.66 (6 H, s, N(CH3)2); see ref. 17. 13C NMR (151 MHz, CDCl3): δ = 158.4 (C1), 157.6 (C8), 149.9 (C3), 147.1 (C1′), 142.6 (C10a), 142.6 (C4a), 141.8 (C1′′), 133.2 (C4′a), 131.4 (C2′′, C6′′), 131.1 (C8′a), 130.5 (C3′′, C5′′), 128.1 (C4′′), 127.8 (C5′), 127.2 (C2′), 126.5 (C6), 126.1 (C8′), 126.0 (C3′), 125.7 (C4′), 124.6 (C6′), 124.3 (C7′), 115.7 (C8a), 107.7 (C5), 105.1 (C9a), 102.6 (C7), 92.8 (C4), 89.7 (C2), 55.2 (C1OCH3), 55.1 (C8OCH3), 40.5 (N(CH3)2), 30.2 (C9). ESI-MS: m/z calcd for C33H31N2O2 +: 487.2380; found: 487.2376 [M + H+]. The enantiomers were separated on a ­Chiracel® OD-H column (4.6 mm x 150 mm; 5 µm; Art. Nr. 14324) using a 1.0 mL/min flow of n-heptane/i-PrOH 95:5: 5.57 and 6.75 min.
  • 15 9-(4-Fluoronaphthalen-1-yl)-1,8-dimethoxy-N,N-dimethyl-10-phenyl-9,10-dihydroacridin-3-amine (5b)Prepared according to the above general procedure. Rf  = 0.74 (CH2Cl2 100%); IR (neat): νmax = 2926s, 1610s, 1468s, 1311w, 1249s, 1091m, 909w. 1H NMR (600 MHz, CDCl3): δ = 8.96 (1 H, d, 3 J = 8.8 Hz, C8′H), 8.04 (1 H, d, 3 J = 8.4 Hz, C5′H), 7.61–7.66 (3 H, m, C7′H, C3′′H, C5′′H), 7.57–7.60 (1 H, m, C2′H), 7.49–7.53 (2 H, m, C6′H, C4′′H), 7.46–7.47 (2 H, m, C2′′H, C6′′H), 6.94–6.98 (1 H, m, C3′H), 6.83–6.86 (1 H, m, C6H), 6.53 (1 H, s, C9H), 6.25 (1 H, d, 3 J = 8.0 Hz, C7H), 5.91 (1 H, d, 3 J = 8.3 Hz, C5H), 5.74 (1 H, d, 4 J = 2.2 Hz, C2H), 5.27 (1 H, d, 4 J = 2.2 Hz, C4H), 3.44 (3 H, s, C1OCH3), 3.43 (3 H, s, C8OCH3), 2.67 (6 H, s, N(CH3)2); see ref. 17. 13C NMR (125 MHz, CDCl3): δ = 158.3 (C1), 157.5 (C8), 156.8 (d, 1 JCF = 247 Hz, C4′), 149.9 (C3), 143.1 (d, 4 JCF = 4.5 Hz, C1′), 142.6 (C10a), 142.5 (C4a), 141.7 (C1′′), 132.1 (d, 3 JCF = 4.1 Hz, C8′a), 131.4 (C2′′, C6′′), 130.5 (C3′′, C5′′), 128.1 (C4′′), 126.7 (d, 3 JCF = 8.4 Hz, C2′), 126.6 (C6), 126.1 (d, 4 JCF = 2.4 Hz, C8′), 125.5 (C7′), 124.9 (d, 4 JCF = 1.3 Hz, C6′), 122.8 (d, 2 JCF = 15.4 Hz, C4′a), 119.9 (d, 3 JCF = 6.3 Hz, C5′), 115.4 (C8a), 109.6 (d, 3 JCF = 19.5 Hz, C3′), 107.7 (C5), 104.8 (C9a), 102.6 (C7), 92.7 (C4), 89.6 (C2), 55.1 (C8OCH3), 55.0 (C1OCH3), 40.5 (N(CH3)2), 30.0 (C9). 19F NMR (471 MHz, CDCl3): δ = –126.8. ESI-MS: m/z calcd for C33H30FN2O2 +: 505.2286; found: 505.2293 [M + H+]. The enantio­mers were separated on a Chiracel® OD-H column (4.6 mm x 150 mm; 5 µm; Art. Nr. 14324) using a 1.0 mL/min flow of n-heptane/i-PrOH 95:5: 5.37 and 6.43 min.
  • 16 NOE enhancements observed between C9H of the acridinium and C8′H of the naphthyl group suggest the structure of the major diastereomer to be rac-5 as shown in Scheme 3.
  • 17 General Procedure for the Oxidation of the leuco-Form A solution of leuco-form 5a or 5b (5.00 μmol) in CH2Cl2 (2.0 mL) was treated at RT with an excess of chloranil and the mixture stirred until the red color persisted. The mixture was washed with water (2.0 mL) and 1 M HBr (2 x 1.0 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography over silica gel with 100% CH2Cl2 and CH2Cl2/MeOH (100:5) to provide acridinium bromide salt 4a or 4b: Sakabe M. Asanuma D. Kamiya M. Iwatate RJ. Hanaoka K. Terai T. Nagano T. Urano Y. J. Am. Chem. Soc. 2013; 135: 409
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    • 18a λabs: 425 nm; λem: 501 nm; E1/2(P*/P–): +2.06 V, E1/2(P/P–): –0.57 V vs. SCE: Tsudaka T. Kotani H. Ohkubo K. Nakagawa T. Tkachenko NV. Lemmetyinen H. Fukuzumi S. Chem. Eur. J. 2017; 23: 1306
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    • 18b λabs: 412 nm, λem: 550 nm; E1/2(P*/P–): +1.62 V and E1/2(P/P–): –0.84 V vs. SCE: Joshi-Pangu A. Lévesque F. Roth HG. Oliver SF. Campeau L.-C. Nicewicz D. DiRocco DA. J. Org. Chem. 2016; 81: 7244
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    • 19a Aliquots treated by NaBH4 allowed the measurement of change in ee% by HPLC over time for rate of racemization (krac ), the barrier to rotation (ΔG ‡ 393K ) and the racemization half-life (t 1/2) determination.
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  • 21 The results reported in this publication form part of a patent application: Fischer C. Sparr C. EP 17188288, 2017
    PubMed