Novel fluorescent isoquinoline derivatives obtained via Buchwald-Hartwig coupling of isoquinolin-3-amines

Isoquinolin-3-amines bearing an alkyl group or hydrogen atom in position 4 easily underwent Buchwald-Hartwig coupling reactions with various substituted aryl halides. Investigation of the selected new derivatives with fluorescent spectroscopy revealed that the reaction products have similar photophysical properties to those of isoquinolin-3-amine except the N -(nitrophenyl) derivatives, which emit negligible fluorescence


Introduction
Recently we have published 1 that some isoquinoline derivatives bearing a morpholine group in position 1 or 3 represent a new group of fluorescent compounds.In the course of continuation of our activity in the area of isoquinolinamines, synthesis of variously substituted Narylisoquinolinamines has been decided.Such compounds could serve as valuable starting compounds for subsequent ring closure reactions.To this end, use of the available isoquinolin-3amine as well its 4-methyl and 4-benzyl derivative in Buchwald-Hartwig amination [2][3][4] of aryl halides has been envisaged.

Results and Discussion
Inspection of the pertinent literature revealed that very few cases of direct amination with isoquinolinamine have been carried out. 5Similarly, Buchwald-Hartwig amination with quinolinamines and pyridinamines and other related N-heterocycles have also been published by the same research group. 6n the frame of the present study, unsubstituted and 4-alkyl substituted isoquinolin-3-amines (1, R 4 = H, CH3 and CH2C6H5, respectively) were treated with various substituted bromobenzene derivatives and 2,3-dibromopyridine as shown in Scheme 1.The substituents of the bromobenzene reagent involved m-and p-Cl, o-, m-, and p-Br, o-and p-NO2, o-, m-, and p-COOEt, o-CHO moieties.As a ligand to Pd2(dba)3 JohnPhos and Xantphos provided the best results.As bases, cesium carbonate and sodium t-butoxide were used.The products have been obtained in 46-94% yields.The derivatives and experimental conditions are summarized in Table 1.

Scheme 1
In order to reveal the photophysical properties of the new compounds, some selected derivatives have been studied by absorption and fluorescence spectroscopy.As shown in Figure 1, the nitro-substitution leads to a significant bathochromic shift of the first absorption band, whereas the introduction of the p-COOC2H5 moiety brings about marked blue-and red-shifts for the first and second absorption bands, respectively.The m-COOC2H5 and p-Cl substituents have smaller effect.Intramolecular hydrogen bonding between N-H and the oxygen of the o-NO2 may contribute to the considerable diminution of the energy of the lowest singlet-excited state in the case of 2l.Table 2 summarizes the photophysical parameters of the new compounds and, for the sake of comparison, those of isoquinolin-3-amine (1, R 4 = H).The fluorescence maximum (max(fl)) exhibits a marked displacement to longer wavelength upon attachment of N-phenyl group to 1a, but max(fl) diminishes in the series of 2a > 2g > 2s > 2t > 1a.The Stokes-shift of the fluorescence band is larger when a substituted phenyl group is attached to the isoquinolinamine skeleton indicating that more substantial structural alteration occurs upon excitation than in the case of 1a.The N-(nitrophenyl) derivatives (2o and 2l) emit negligible fluorescence due probably to the enhanced charge transfer character of the lowest singlet-excited state.The new compounds have slightly smaller fluorescence quantum yields (f) and somewhat longer fluorescence lifetimes (f) than 1a, 1 but neither of these quantities is sensitive to the COOC2H5 or Cl substitution.The rate constant of fluorescence emission (kf) and radiationless deactivation (knr) from the singlet excited state were calculated using kf = f/f and knr = (1-f)/f relationships, respectively.As seen in Table 2, practically constant knr values were obtained for all fluorescent derivatives, whereas kf is slightly larger for 1a compared to the corresponding values of the phenylamino derivatives.

Conclusions
The present results reveal that a great number of actively fluorescent phenylamino and pyridylaminoisoquinolines can be easily obtained by one single manipulation starting from isoquinolinamines in medium to excellent yields.The quantum yield and lifetime of the fluorescence are insensitive to the substituent of the N-phenyl moiety but introduction of nitro group makes the compound practically nonfluorescent.

Experimental Section
General.Melting points were determined on a Büchi apparatus.The IR spectra were recorded on a Thermo Nicolet Avatar 320 FT-IR spectrometer.NMR measurements were performed on Varian INOVA-300 spectrometer equipped with a 5 mm inverse detection z-gradient probe. 1 H and 13 C NMR spectra were measured at room temperature (25 °C) in an appropriate solvent. 1 H and 13 C chemical shifts are expressed in ppm (δ) referenced to TMS or residual solvent signals.
The elemental analysis has been carried out with an Elementar Vario EL III apparatus (at the Analytical Laboratory for Organic Chemistry, Chemical Research Center, Hungarian Academy of Sciences, H-1025 Budapest, Pusztaszeri út 59-67).Reactions were monitored with Merck silica gel 60 F254 tlc plates (0.25 mm thickness).All the chemicals and solvents were used as supplied.The UV-visible absorption spectra were recorded on a Unicam UV 500 spectrophotometer.Corrected fluorescence spectra were obtained on a Jobin-Yvon Fluoromax-P photoncounting spectrofluorometer.Fluorescence lifetimes were measured with time-correlated single-photon counting technique as described previously. 7Fluorescence quantum yield was determined relative to that of quinine sulfate in 1 N H2SO4, for which a reference yield of f = 0.546 was taken. 8
After cooling down to room temperature, the reaction mixture was concentrated and the residue was purified by flash column chromatography on silica gel.

Table 1 .
Various 2l Figure 1.Absorption spectra of 2a (thin line), 2t (thick line), 2o (thick dash line) and 2l (thin dash line) in acetonitrile.Inset shows the zoomed view of the long wavelength range.

Table 2 .
Photophysical properties of the selected isoquinolin-3-amines in acetonitrile bThe location of the maximum of the lowest-energy absorption band, c shoulder, d fluorescence is too weak to determine precisely.