A Convenient Approach to meso-Uracil–4,4-Difluoro-4-bora-3a, 4a-diaza-s-indacene Derivatives

M. Trapani; M. A. Castriciano; J. A. A. W. Elemans; A. Nicosia; P. Mineo; M. Cordaro

doi:10.1055/a-1545-7086

Synlett, Inhaltsverzeichnis

Synlett 2021; 32(17): 1714-1718
DOI: 10.1055/a-1545-7086

letter

A Convenient Approach to meso-Uracil–4,4-Difluoro-4-bora-3a, 4a-diaza-s-indacene Derivatives

M. Trapani

^aCNR- ISMN Istituto per lo Studio dei Materiali Nanostrutturati, c/o Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche e Ambientali, 98166 V. le F. Stagno D’Alcontres 31, Messina, Italy

,

M. A. Castriciano

^aCNR- ISMN Istituto per lo Studio dei Materiali Nanostrutturati, c/o Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche e Ambientali, 98166 V. le F. Stagno D’Alcontres 31, Messina, Italy

,

J. A. A. W. Elemans

^bInstitute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ, Nijmegen, the Netherlands

,

A. Nicosia

^cDipartimento di Scienze Chimiche, University of Catania, V. A. Doria 6, 95100 Catania, Italy

,

P. Mineo

^cDipartimento di Scienze Chimiche, University of Catania, V. A. Doria 6, 95100 Catania, Italy

^dCNR-IPCF Istituto per i Processi Chimico-Fisici, V.le F. Stagno D’Alcontres 37, I-98158 Messina, Italy

,

M. Cordaro ∗

^eDipartimento di Scienze Chimiche, Biologiche, Farmaceutiche e Ambientali, 98166 V. le F. Stagno D’Alcontres 31, University of Messina, Messina, Italy

› Institutsangaben

Abstract

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Abstract

An effective and convenient protocol for the synthesis of 1-substituted uracil-6-carbaldehyde derivatives has been developed. A three-step sequence permits the preparation of uracil-6-carbaldehydes with various substituents at the N-1 in large quantities by using low-cost precursors. The aldehyde-functionalized uracils served as useful precursors for the preparation of meso-(1-substituted 6-uracil)-derivatives of 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY). In this way, regioselectively functionalized BODIPYs with a direct connection to a nucleobase were prepared in yields of 30–45%. MALDI-TOF mass spectrometry, NMR, UV/vis absorption, and steady-state and time-resolved fluorescence spectroscopies were used to characterize the structures and the spectroscopic/photophysical properties of the resultant dyes.

Key words

difluoroboradiazaindacenes - aldehydes - dyes - atropisomerism - formyluracils

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Referenzen

References and Notes

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17 1-Butyluracil-6-carbaldehyde (3a) 1-Butyl-6-methyluracil (2a; 200 mg, 1 mmol) and SeO₂ (113 mg, 1 mmol) were dissolved in 10% HOAc–1,4-dioxane (10 mL), and the mixture was stirred at 100 °C for 3 h. The product was purified by column chromatography (silica gel, 10% MeOH–CH₂Cl₂) to give a pale-yellow solid; yield: 195 mg (45%); mp 145–146 °C (Lit.¹¹ 146–147 °C). IR (neat): 3163, 3031, 2954, 2931, 2871, 2803, 1715, 1691, 1664, 1477, 1365, 1170, 1034, 963, 862, 803, 761, 727, 636, 524 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 9.57 (s, 1 H, CH), 8.92 (br s, 1 H, NH), 6.24 (s, 1 H, CH), 4.19 (t, J = 7.8 Hz, 2 H, CH₂), 1.61–1.55 (m, 2 H, CH₂), 1.41–1.33 (m, 2 H, CH₂), 0.95 (t J = 7.6 Hz, 3 H, CH₃). ¹³C NMR (125 MHz, CDCl₃): δ = 185.5, 164.4, 151.9, 146.9, 114.4, 43.7, 31.5, 19.7, 13.6. MALDI-TOF: m/z = 197.5 [M + H]⁺. 1-Hexyluracil-6-carbaldehyde (3b); Typical Procedures Method A: Compound 3b was prepared by the same procedure as 3a, starting from 2b (100 mg, 0.45 mmol) and SeO₂ (50 mg, 0.45 mmol); yield: 43 mg (40%); pale-yellow solid; mp 149–150 °C. Method B: A suspension of 1-hexyluracil (8b; 200 mg, 1 mmol) in anhyd THF was stirred in a dry-ice bath (–78 °C) under argon. A 1 M solution of LDA in THF (10 mL) was added dropwise over 1 h, then HCO₂Et (165 mL, 2 mmol) was slowly added from a syringe. The mixture was kept at –78 °C for 3 h then warmed to r.t. HOAc was added to neutralize excess base, and the mixture was filtered. The solvent was removed by rotary evaporation, and the crude product was purified by column chromatography (silica gel, 20% EtOAc–CH₂Cl₂) to give a yellow liquid; yield: 34 mg (15%). IR (KBr): 3129, 3073, 2965, 2925, 2858, 2781, 1709, 1659, 1645, 1601, 1474, 1396, 1371, 1182, 1057, 909, 836, 763, 720, 622, 544, 516 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 9.57 (s, 1 H, CH), 8.96 (s, 1 H, NH), 6.24 (s, 1 H, CH), 4.18 (t, J = 7.9 Hz, 2 H, CH₂), 1.61–1.58 (m, 2 H, CH₂), 1.35–1.31 (m, 6 H, CH₂), 0.89 (t, J = 7.2 Hz, 3 H, CH₃). ¹³C NMR (125 MHz, CDCl₃): δ = 185.6, 162.4, 151.1, 146.9, 114.5, 43.9, 29.4, 26.1, 22.5, 19.9, 13.9. ESI-MS: m/z = 279.1 [M + CH₃OH + Na]⁺.
18 Uracil–BODIPY Derivatives 4; General Procedure The appropriate 1-substituted uracil-6-carbaldehyde 3 (1 equiv), DMP (2.1 equiv), and a catalytic amount of TFA were dissolved in anhyd CH₂Cl₂, and the mixture was stirred under argon at r.t. for 24 h. A solution of p-chloranil (1 equiv) in CH₂Cl₂ was added from a syringe, and the mixture was stirred for 1 h. Et₃N (9 equiv) and BF₃∙Et₂O (6 equiv) were then added, and the mixture was stirred overnight. The organic fraction was washed with sat. aq NaHCO₃ (50 ml), brine, and water, and the combined organic layers were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The resulting mixture was purified by column chromatography (silica gel, gradient 10–30% EtOAc–CH₂Cl₂). 1-Butyluracil–BODIPY (4a) Prepared according to the general procedure from 3a (38 mg, 0.2 mmol) as a dark-red solid; yield: 28 mg (35%); mp 261–265 °C. IR (neat): 3156, 3035, 2960, 2926, 2874, 2798, 1714, 1670, 1541, 1509, 1457, 1410, 1309, 1187, 1152, 1053, 972, 798, 755, 607, 527, 475 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 9.66 (s, 1 H, NH), 6.12 (s, 2 H, CH), 5.84 (s, 1 H, CH), 3.70 (t, J = 8.2 Hz, 2 H, CH₂), 2.57 (s, 6 H, CH₃), 2.07 (s, 6 H, CH₃), 1.52–1.48 (m, 2 H, CH₂), 1.25–1.19 (m, 2 H, CH₂), 0.76 (t, J = 7.5 Hz, 3 H, CH₃). ¹³C NMR (125 MHz, CDCl₃): δ = 162.2, 158.7, 151.1, 149.9, 141.7, 129.4, 127.8, 122.6, 103.7, 46.0, 30.2, 19.7, 14.9, 14.3, 13.2. MALDI-TOF: m/z = 415.4 [M + H]⁺.

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