Mild Synthesis of Fluorosolvatochromic and Acidochromic 3-Hydroxy

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Mild Synthesis of Fluorosolvatochromic and Acidochromic 3-Hydroxy-4pyridylisoquinoline Derivatives from Easily Available Substrates Gabriel Enrique Gomez Pinheiro, Heiko Ihmels, and Christoph Dohmen J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03272 • Publication Date (Web): 31 Jan 2019 Downloaded from http://pubs.acs.org on February 4, 2019

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The Journal of Organic Chemistry

Mild Synthesis of Fluorosolvatochromic and Acidochromic 3Hydroxy-4-pyridylisoquinoline Derivatives from Easily Available Substrates Gabriel E. Gomez Pinheiro, Heiko Ihmels,* and Christoph Dohmen Department of Chemistry and Biology, and Center of Micro and Nanochemistry and Engineering, University of Siegen, Adolf-Reichwein-Str. 2, 57068 Siegen, Germany; e-mail: [email protected]

TOC graphic: R1 NaNCO

N R1

DMF, r.t. HO 6.5–23 h N 9 examples

N

R2

R2

fluorosolvatochromism

acidochromism

H 2O MeOH EtOH MeCN THF

acidic neutral basic

Abstract. The reaction of sodium cyanate with benzo[b]quinolizinium substrates at room temperature gave 3-hydroxy-4-pyridyl-3-isoquinoline derivatives in good yields. Presumably, the overall reaction proceeds through an ANRORC-type sequence, i.e. addition of the nucleophile, ring opening, and ring closure. Preliminary photophysical investigation of the parent compound revealed a pronounced sensitivity of its emission properties toward solvent effects and the pH of the medium.

Isoquinolines are attractive and promising lead structures in drug discovery. As a result, several 1

synthetic approaches have been established for the synthesis of isoquinoline derivatives. At the same 2

time, it is surprising that mild synthetic routes to 3-hydroxyisoquinolines (and for that matter the tautomeric isoquinolin-3-ones) are rather rare, although this class of compounds has been shown also to exhibit attractive biological activity and useful photophysical properties. Thus, 3-hydroxyisoquinoline 3

4

derivatives are available by the traditional cyclization methods – usually under harsh conditions – with the formation of the N-heterocyclic ring as the key step. If necessary, the initially formed 5

tetrahydroisoquinolinol has to be subsequently oxidized. More recently, it has been demonstrated that 6

1 ACS Paragon Plus Environment

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3-hydroxyisoquinolines are available with significantly milder methods, for example from B(C F )-/Co6

5

catalyzed C-H bond activation reactions of imines with diazo compounds or by a sequence of Ugi 7

reaction and Pd-mediated Heck cyclization. Herein, we present a novel synthetic route to 3-hydroxy8

isoquinoline derivatives, that we incidentally discovered in failed attempts to functionalize halogenated benzo[b]quinolizinium derivatives 1b–e by nucleophilic substitution

9,10

As this appeared to be an

efficient and mild access to the 3-hydroxyisoquinoline structure from readily available starting materials, we further investigated this route. In the following, we present the scope and limits of this 11

reaction, along with a representative demonstration that the 4-pyridyl-3-hydroxyisoquinoline structure exhibits promising medium-sensitive absorption and emission properties. 5' 6'

R1 N

R2

NaNCO DMF r.t. 6.5–23 h

1a–l

NCO N 1m

3' 2' 4

HO

5

3

R1 6 7

N 1

8

R2

2a–l

1b: R1 = F, R 2 = H DMF r.t.

NaNCO

4'

N

a : R1 = R 2 = H (74%) b : R1 = F, R 2 = H (64%) c : R1 = Cl, R 2 = H (64%) d : R1 = Br, R 2 = H (63%) e : R1 = H, R 2 = F (70%) f : R1 = NO 2, R 2 = H (12%) g : R1 = CO 2H, R 2 = H (76%) h : R1 = Ph, R 2 = H (88%) i : R1 = OMe, R 2 = H (8%) j : R1 = NHPh, R 2 = H (1%) k : R1 = NH 2, R 2 = H (n.r.) l : R1 = OH, R 2 = H (n.r.)

Scheme 1. Synthesis of 3-hydroxyquinoline derivatives 2a–k (n.r. = no reaction)

The reaction of 9-fluorobenzo[b]quinolizinium (1b) with 1.3 molar equiv. of sodium cyanate gave a 12

yellow fluorescent product. Notably, NMR-spectroscopic analysis revealed that the expected substitution product 1l was not formed, as the characteristic signals of benzo[b]quinolizinium derivatives were not observed. Instead, a detailed 2D-NMR analysis revealed the presence of a pyridyl 13

ring and an isoquinoline unit, that is substituted in positions 3, 4 and 6 as seen from the characteristic shifts and multiplicities of the NMR signals at 7.20, 8.09 and 8.96 ppm (cf. SI). Additional massspectrometric analysis as well as elemental analysis data were consistent with the structure of 6-fluoro4-(2-pyridyl)-3-hydroxyisoquinoline (2b). To assess whether the reaction of the benzo[b]quinolizinium 2 ACS Paragon Plus Environment

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ion with cyanates is a general synthetic route to 4-(2-pyridyl)-3-hydroxyisoquinoline derivatives, we examined the reaction of different benzo[b]quinolizinium derivatives 1a–k with sodium cyanate (Scheme 1). Thus, the reactions of the parent compound 1a and of acceptor-substituted derivatives 1b– g gave the corresponding hydroxypyridylisoquinoline derivatives 2a–g in good yields (63–74%), except for the nitro-substituted derivative that could only be isolated in 12% yield. The reactions proceeded smoothly at room temperature, and the products were isolated by column chromatography and subsequent crystallization. All products were identified and fully characterized by 1D- and 2DNMR spectroscopy and mass spectrometry. It should be noted that in the case of nitro-, carboxy- and phenyl-substituted derivatives 1f–h, elemental analysis data did not match the theoretical values; however, the spectroscopic data and comparison with the ones of the other derivatives 1a–e supported the proposed structures of 1f–h (cf. SI). In contrast, the reaction with donor-substituted benzo[b]quinolizinium derivatives is inefficient. Thus, the amino- and hydroxy-substituted derivatives 1j and 1k do not react at all, even at elevated temperatures, and the reaction of the methoxy-substituted substrate 1i gave the product 2i only in very low yield of 8%. The formation of the 3-hydroxyisoquinoline structure from the reaction of benzo[b]quinolizinium with isocyanates may be explained by an initial nucleophilic attack at the meso position C6 to give the intermediate Int1 followed by a ring opening reaction to give Int2 (Scheme 2). This type of reaction with strong nucleophiles, such as the hydroxide anion, amines, cyanide or carbanions, is well known 14

15

16

for benzo[b]quinolizinium derivatives. In some of these cases, consecutive products could be isolated.

17

But in the case of cyanide, which is the closest analogue to the cyanate employed in this study, the structure of the primary addition product has not been fully proven and secondary reaction products could not be completely identified. In the case of the reaction with cyanate, however, the intermediate 16

Int2 is proposed to be formed that has the structural prerequisites for a ring closure to give the dihydroquinolone Int3, so that the overall reaction constitutes a special case of an ANRORC sequence (addition of nucleophile, ring opening, ring closure). Notably, the structure of Int3 is likely 18



1

11

10

2

9

N

3 4

8 6

7

NCO 1a

N NCO Int1

N

N O C N

N Int2

N

± H+ H

O

Page 4 of 18

N

HO

O N

Int3

HN 2aLactam

2a

Scheme 2. Proposed mechanism for the formation of 4-pyridyl-3-hydroxyisoquinoline (2a) from the reaction of benzo[b]quinolizinium (1a) with cyanate.

not the most stable stereoisomer – with regard to the Z configuration of the isocyanato-substituted exomethylene group – that may be formed on ring opening, but as all reaction steps are reversible, we propose that there is always sufficient amount of this intermediate formed in the equilibrium state. Finally, tautomerization of Int3 leads to the formation of the 3-hydroxy-4-pyridylisoquinoline 2a. The reduced reactivity of the donor-substituted benzo[b]quinolizinium derivatives may also be explained by the proposed reaction mechanism. The donor substituent at position 9 significantly diminishes the electrophilicity of the meso position C6, as shown by the increase of the net atomic charge on this position, so that the addition of the nucleophile at this position is strongly retarded. It should be noted 19

that the low yield of the acceptor-substituted nitro-substituted derivative 1f seems to be inconsistent with this proposed mechanism, as acceptor substituents should facilitate the reaction. However, the given yield refers to the isolated product with sufficient analytical purity, and the low yield of actually isolated derivative 1f does not document its high yield of formation (as indicated by the H-NMR 1

spectrum of the product mixture, cf. SI), but instead reflects to the difficult purification of this product. The absorption and emission spectra of the parent pyridyl-3-hydroxyisoquinoline 2a were recorded in different solvents (Table 1, Figure 1 and 2). In solvents with moderate polarity, a single maximum between 353 nm (1,4-dioxane) and 365 nm (CHCl ) was observed, whereas in more polar solvents two 3

absorption maxima were detected with one band centered at 352–355 nm and an additional red-shifted band with maxima ranging from 420 nm (MeOH) to 449 nm (DMSO). These two absorption bands have similar magnitude in alcohol solution while the blue-shifted band is more intense in polar, aprotic 20

solvents. In water, only the red-shifted absorption maximum appeared at 408 nm. The emission spectra of 2a in acetone, chloroform, 1,4-dioxane, THF and EtOAc show one band with a maximum around 399 nm, in some cases accompanied by a very weak tail with zero onset between 450 and 550 nm 4 ACS Paragon Plus Environment

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(Figure 2, cf. SI). In alcohol, DMSO or DMF solution, however, dual emission was observed in which the red-shifted band at 519 nm (ROH) and 529 nm (DMSO, DMF) is as intense as the blue-shifted one. In water, only one emission band was observed with a maximum at 505 nm. Most notably, these distinct emission colors of 2a in different solvents are observable with the naked eye (Figure 2). Overall, the absorption and emission properties of 2a, especially the solvent-dependent formation of two distinct long-wavelength absorption and emission bands, resemble the ones of the parent 3hydroxyisoquinoline. In the latter case, the different bands have been assigned to the lactam ("keto") 21

and lactim ("enol") form, which are in a tautomeric equilibrium. Considering the close resemblance of the spectra of 3-hydroxyisoquinoline and 2a the absorption and emission bands of the latter are assigned likewise, namely the red-shifted band corresponds to the lactam form 2a

Lactam

and the blue-

shifted one to the lactim 2a (Scheme 2). Table 1. Absorption and Emission Maxima of 4-Pyridyl-3-hydroxyisoquinoline (2a) Solvent

λ / nm

a

λ / nm

b,c abs

d em

λ / nm e em

Φ

em

– Water 408 505 0.10 519 MeOH 354 (420) 398 0.09 519 EtOH 354 (427) 401 0.10 – MeCN 355 (448) 395 0.10 529 DMSO 353 (449) 411 0.23 529 DMF 352 (446) 411 0.21 – Acetone 355 (448) 399 0.16 – CHCl 365 398 0.01 – EtOAc 356 398 0.15 – THF 355 401 0.41 – 1,4-Dioxane 353 398 0.29 Solvents listed in order of decreasing polarity. Absorption maximum with highest energy, c = 10 M. Absorption maximum in brackets refer to the red-shifted band from prototropic equilibrium species. Dual emission: Blue-shifted emission maximum. Dual emission: Red-shifted emission maximum, c = 10 M. Fluorescence quantum yield relative to Coumarin 153 (Φ = 0.38 in EtOH), λ = 420 nm, estimated error: ±10% of the given values. Measured only for red-shifted band. Fluorescence quantum yield relative to anthracene (Φ = 0.29 in EtOH), λ = 355 nm, estimated error: ±10% of the given values. f

f, g

f, g

h

h

h

h

h

3

h

h

h

a

b

–4

c

d

e

f

–5

em

g

em

ex

h

ex



Page 6 of 18

Figure 1. Absorption (A, c = 0.1 mM) and emission spectra (B, c = 10 µM) of 2a in different solvents (red: water; black: MeOH; magenta: THF; green: DMSO).

Figure 2. Emission colors of 2a in different solvents.

Considering the different acidic and alkaline positions of the molecule, the absorption and emission spectra of 2a were determined at different pH values in Britton-Robinson buffer. With the variation of 22

pH values, the absorption and emission properties of 2a change significantly. Hence, with increasing pH from 2 to 12, the absorption maximum at 429 nm decreased and a new band with absorption maximum at 409 nm was formed around pH 7, which is in good agreement with the absorption in water. Further increase of the pH value led to the formation of a new band at 383 nm at pH > 10 (Figure 3). The emission spectra exhibit a similar pH-dependent development as the absorption spectra, thus indicating that these data only reflect the prototropic equilibria in the ground state. At pH 2, an emission band was observed at 530 nm which decreased to a blue-shifted emission band at 505 nm at pH 7. The latter band disappeared with further increase of the pH value in favor of a band at 488 nm at pH > 10. The analysis of the isotherms from photometric titrations revealed two distinct pK values, pK a

a1

= 4.2 and pK = 9.4 (cf. SI, Figure S2). The pK value is in good agreement with the reported one of the a2

a2

parent 3-hydroxyisoquinoline and can be assigned to the hydroxy functionality. The pK value may 23

a1

relate to the pyridine or isoquinoline unit, as both should have similar basicity; but from


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Figure 3. Photometric (A) and fluorimetric (B) acid-base titration of 2a (c = 100 µM) in BrittonRobinson buffer (pH 2–12) with aq. NaOH (c = 2.00 M). Arrows indicate the development of bands with increasing pH of the solution. Insets: Dependence of the absorption and relative fluorescence intensity on the pH of the solution and emission color at different pH (bottom inset in B). NaOH

the experimental titration data a conclusive assignment is not possible. Notably, the pH-dependence of the absorption and emission properties of 2a is different from the one of the parent 3hydroxyisoquinoline, especially at acidic conditions. The absorption and emission maxima of the latter 24

are blue-shifted upon acidification. In contrast, 2a exhibits significant red-shifts of both absorption and emission maxima, most likely resulting from protonation of the pyridyl substituent, which in turn leads to the development of a more pronounced donor-acceptor interplay between the hydroxy group (donor) and the pyridine/pyridinium (acceptor). As a result, the emission color of 2a changes significantly at 25

acidic and alkaline pH values, which is clearly visible to the naked eye (Figure 3, inset). Considering the photoacidic properties of hydroxy-substituted hetarenes an excited-state intramolecular proton 26

transfer (ESIPT) between the hydroxy group and the pyridine in 2a may also be considered. 27

Nevertheless, the steady-state emission properties (Figures 2 and 3) do not allow a conclusive identification of an ESIPT process, so that more detailed time-resolved studies are necessary. In summary, we present a straightforward and very mild synthetic route to 3-hydroxy-4-pyridyl-3isoquinoline derivatives that starts from readily available precursor molecules and that does not require additional catalysts. Considering the availability of starting materials with different substitution patterns, this approach offers the opportunity to synthesize a large variety of differently substituted isoquinoline derivatives, that may be used, for example, to assess structure-activity relationships in systematic biological tests. Furthermore, the preliminary photophysical investigation of the derivative 2a revealed a pronounced sensitivity of its emission properties toward solvent effects and the pH of the 7 ACS Paragon Plus Environment


Page 8 of 18

medium. Therefore, we conclude that this class of fluorosolvatochromic compounds constitute a promising foundation for the development as medium-sensitive fluorescent probes, that operate both in water and in organic solvents.

Experimental Section General Instrumentations and Materials The employed chemicals (Sigma-Aldrich, Acros or Alfa Aesar) were reagent grade and used without further purification. NMR spectroscopy: Varian VNMR-S 600 ( H: 600 MHz, C: 150 MHz, T = 25 1

13

°C), Jeol ECZ 500 ( H: 500 MHz, C: 125 MHz, T = 25 °C), Bruker AV 400 ( H: 400 MHz, C: 100 1

13

1

13

MHz, T ≈ 22 °C). The chemical shifts are given relative to the solvent peak in ppm (DMSO-d : H = 1

6

2.50, C = 39.5; CDCl : H = 7.26, C = 77.2). Elemental analyses: HEKAtech EUROEA combustion 13

1

13

3

analyzer, conducted by Mr. Rochus Breuer (Universität Siegen, Organische Chemie I). Melting points: BÜCHI 545 (BÜCHI, Flawil, CH); uncorrected. HRMS: Exactive Orbitrap Mass Spectrometer. Solvents employed in spectroscopic experiments were of spectral grade; deionized water (resistivity ρ ≥ 18 MΩ cm- ) was used for the preparation of buffer solutions. 1

Synthesis All commercially available chemicals (Sigma-Aldrich, Acros or Alfa Aesar) were reagent grade and used without further purification. The benzo[b]quinolizinium substrates were prepared according to literature procedures: Benzo[b]quinolizinium bromide (1a), 9-fluorobenzo[b]quinolizinium bromide 28

(1b), 9-chlorobenzo[b]quinolizinium bromide (1c), 9-bromobenzo[b]quinolizinium bromide (1d), 812

fluorobenzo[b]quinolizinium

27

bromide

(1e),

27

27

9-nitrobenzo[b]quinolizinium

perchlorate

(1f),

benzo[b]quinolizinium-9-carboxylic acid (1g), 9-phenylbenzo[b]quinolizinium bromide (1h), 28

29

11

9-

methoxybenzo[b]quinolizinium tetrafluoroborate (1i), 9-aminobenzo[b]quinolizinium bromide (1j), 30

31

9-hydroxybenzo[b]quinolizinium tetrafluoroborate (1k).

32

General procedure for the synthesis of 4-(2-pyridyl)-3-hydroxyisoquinolines 8 ACS Paragon Plus Environment

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A solution of the benzo[b]quinolizinium derivative (1.00 mmol) and sodium isocyanate (1.30 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 6.5–23 h. After evaporation of the solvent the residue was submitted for column chromatography. The solvents were evaporated and the residue was recrystallized to obtain the product. 4-(2’-Pyridyl)-3-hydroxyisoquinoline (2a). Chromatography: SiO , CH Cl /MeOH 0% to 10% 2

2

2

MeOH. Recryst. from toluene to give the product as yellow needles (164 mg, 74%), mp 220-221 °C. H NMR (DMSO-d , 600 MHz): δ = 7.29–7.35 (m, 1 H, 7-H), 7.40 (ddd, J = 8 Hz, J = 5 Hz, J = 1 Hz,

1

3

4

5

6

1 H, 5'-H), 7.51–7.50 (m, 2 H, 5-H, 6-H), 7.60 (d, J = 8 Hz, 1 H, 3'-H), 7.91 (td, J = 8 Hz, J = 2 Hz, 1 3

3

4

H, 4'-H), 7.99 (d, J = 8 Hz, 1 H, 8-H), 8.73 (dd, J = 5 Hz, J = 1 Hz, 1 H, 6'-H), 8.97 (s, 1 H, 1-H), 3

3

5

11.26 (br. s, 1 H, OH). – C{ H} NMR (DMSO-d , 150 MHz): δ = 112.2 (C4a), 122.1 (C5'), 123.1 13

1

6

(C5), 123.2 (C7), 123.3 (C8a), 126.5 (C3'), 128.1 (C8), 130.9 (C6), 136.3 (C4'), 137.5 (C3), 149.1 (C6'), 149.8 (C1), 154.6 (C2'), 157.8 (C4). – El. Anal. calcd. (%) for C H N O (222.3): C 75.66, H 4.54, 14

10

2

N 12.60; found: C 75.57, H 4.33, N 12.56. 6-Fluoro-4-(2-pyridyl)-3-hydroxyisoquinoline (2b). Chromatography: SiO , EtOAc/Hexane 1:1. 2

Recryst. from 2-PrOH as yellow needles (154 mg, 64%), mp 222-223 °C. H NMR (600 MHz, DMSO1

d ): δ = 7.27–7.07 (m, 2 H, 7-H, 5-H), 7.40 (ddd, J = 8 Hz, J = 5 Hz, J = 1 Hz, 1 H, 5'-H), 7.65 (d, J = 3

6

4

5

3

8 Hz, 1 H, 3'-H), 7.91 (dt, J = 8 Hz, J = 2, 1 H, 4'-H), 8.09 (dd, J = 9 Hz, J = 6 Hz, 1 H, 8-H), 8.73 3

4

3

H-F

(ddd, J = 5 Hz, J = 2 Hz, J = 1 Hz, 1 H, 6'-H), 8.96 (s, 1 H, 1-H), 11.64 (br. s, 1 H, OH). – C{ H} 3

4

5

13

1

NMR (150 MHz, DMSO-d ): δ = 106.1 (d, J = 23 Hz, C7), 113.7 (d, J = 27 Hz, C5), 120.2 (C8a), 6

C-F

C-F

122.2 (C4'), 126.6 (C3'), 132.2 (d, J = 11 Hz, C8), 136.4 (C4'), 139.2 (d, J = 11 Hz, C6), 149.1 (C6'), C-F

C-F

149.2 (C1), 154.2 (C2'), 158.4 (C4a), 162.3 (C4), 164.7 (C3). – El. Anal. calcd. (%) for C H N OF 14

9

2

(240.2): C 69.99, H 3.78, N 11.66; found: C 70.05, H 3.55, N 11.55. 6-Chloro-4-(2-pyridyl)-3-hydroxyisoquinoline (2c). Chromatography: SiO , CH Cl /MeOH 95:5. 2

2

2

Recryst. from 2-PrOH/hexane as yellow needles (164 mg, 64%), mp 225-226 °C. H NMR (600 MHz, 1

CDCl ): δ = 7.29 (dd, J = 9 Hz, J = 2 Hz, 1H, 7-H), 7.38 (ddd, J = 8 Hz, J = 5 Hz, J = 1 Hz, 1H, 5'3

4

3

3

4

3

H), 7.81 (d, J = 9 Hz, 1H, 8-H), 7.85 (d, J = 8 Hz, 1H, 3'-H), 7.93–7.95 (m, 2H, 4'-H, 5-H), 8.77 (d, J 3

3

3



Page 10 of 18

= 6 Hz, 1H, 6'-H), 8.86 (s, 1H, 1-H), 13.74 (br. s, 1 H, OH). – C{ H} NMR (150 MHz, CDCl ): δ = 13

1

3

109.5 (C4), 122.2 (C5), 122.5 (C5'), 122.7 (C8a), 125.1 (C7), 126.1 (C3'), 130.4 (C8), 137.4 (C4'), 137.9 (C5a), 138.6 (C6), 148.7 (C6'), 150.8 (C1), 154.5 (C2'), 160.7 (C3). – El. Anal. calcd. (%) for C H N OCl (256.7): C 65.51, H 3.53, N 10.91; found: C 65.35, H 3.34, N 11.19. 14

9

2

6-Bromo-4-(2-pyridyl)-3-hydroxyisoquinoline (2d). Chromatography: SiO , CH Cl /MeOH 0% to 2

2

2

5% MeOH. Recryst. from toluene as pale yellow needles (190 mg, 63%), mp 229-230 °C. H NMR 1

(DMSO-d , 600 MHz): δ (ppm) = 7.38–7.45 (m, 2 H, 7-H, 5'-H), 7.65 (d, J = 8 Hz, 1 H, 3'-H), 7.73 (d, 2

6

J = 2 Hz, 1 H, 5-H), 7.92 (td, J = 8 Hz, J = 2 Hz, 1 H, 4'-H), 7.94 (d, J = 9 Hz, 1 H, 8-H), 8.67-8.80

4

2

4

2

(m, 1 H, 6'-H), 8.98 (s, 1 H, H-1), 11.63 (br. s, 1 H, OH) . - C{ H} NMR (DMSO-d , 150 MHz): δ = 13

1

6

111.5 (C4), 121.2 (C8a), 122.3 (C5'), 124.9 (C5), 125.6 (C4a), 126.1 (C7), 126.6 (C3'), 130.6 (C8), 136.4 (C4'), 138.5 (C6), 149.1 (C6'), 149.8 (C1), 153.9 (C2'), 158.5 (C3). - El. Anal. calcd. (%) C H N OBr (301.1): C 55.84, H 3.01, N 9.30; found: C 55.77, H 2.77, N 9.23. 14

9

2

7-Fluoro-4-(2-pyridyl)-3-hydroxyisoquinoline (2e). Chromatography: SiO , CH Cl /MeOH 95:5; 2

2

2

yield 70%. Recryst. from 2-PrOH/Hexane as yellow needles (168 mg, 70%), mp 227-228 °C. H NMR 1

(600 MHz, DMSO-d ): δ = 7.42 (ddd, J = 8 Hz, J = 5 Hz, J = 1 Hz, 1H, 5'-H), 7.47 (td, J = 9 Hz, J = 3

6

3

4

3

5

3 Hz, 1H, 5-H), 7.65–7.58 (m, 2H, 8-H, 3'-H), 7.80 (dd, J = 9 Hz, J = 3 Hz, 1H, 6-H), 7.92 (td, J = 8 3

4

3

Hz, J = 2 Hz, 1H, 4'-H), 8.73 (ddd, J = 5 Hz, J = 2 Hz, J = 1 Hz, 1H, 6'-H), 8.96 (s, 1H, 1-H), 11.17 4

3

4

5

(br. s, 1 H, OH). - C{ H} NMR (150 MHz, DMSO-d ): δ = 110.4 (d, J = 20 Hz, C6), 121.5 (C5), 13

1

122.3 (C5'), 126.4 (d, J 1

C-F

2

6

C-F

= 8 Hz, C3') , 126.4 (C8), 126.6 (C7), 134.7 (C8a), 136.4 (C4'), 149.1 (C6'),

149.9 (C1), 154.2 (C2'), 156.9 (C4), 157.6 (C3), 158.6 (C4a). - El. Anal. calcd. (%) C H N OF 14

9

2

(240.23): C 69.99, H 3.78, N 11.66; found: C 69.96, H 3.41, N 11.85. 6-Nitro-4-(2-pyridyl)-3-hydroxyisoquinoline (2f). Chromatography: CHCl /MeOH 9:1. Obtained as 3

red powder (32.1 mg, 12%). H NMR (500 MHz, DMSO-d ): δ = 7.48 (ddd, J = 8 Hz, J = 5 Hz, J = 1 1

3

4

5

6

Hz, 1H, 5'-H), 7.75 (d, J = 8 Hz, 1H, 4'-H), 8.03-7.93 (m, 2H, 7-H, 3'-H), 8.27 (d, J = 9 Hz, 1H, 8-H), 8.53 (d, J = 2 Hz, 1H, 5-H), 8.79 (dt, J = 5 Hz, J = 2 Hz, 1H, 6'-H), 9.21 (s, 1H, H-1). - C{ H} NMR 13

1

(125 MHz, DMSO-d ): δ = 116.1 (C7), 120.0 (C5), 122.7 (C5'), 125.3 (C8a), 126.8 (C4'), 131.0 (C8), 6


Page 11 of 18 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


136.5 (C4a), 136.6 (C3'), 148.9 (C6), 149.3 (C6'), 150.7 (C1), 153.3 (C2'), 159.0 (C3). – HRMS (ESI) calcd for C H N O [M + H ]: 268.0717; found: 268.0727. +

14

10

3

3

3-Hydroxy-4-(2-pyridyl)-6-isoquinoline carboxylic acid (2g). Chromatography: CH Cl /MeOH 9:1. 2

2

Obtained as a yellow solid (202 mg, 76%). H-NMR (400 MHz, DMSO-d ): δ = 7.43 (dd, J = 7 Hz, J = 1

3

3

6

5 Hz, 1 H, 4'-H), 7.62 (d, J = 8 Hz, 1 H, 6'-H) 7.79 (d, J = 8 Hz, 1 H, 7-H) 7.93 (td, J = 8 Hz, J = 1 3

3

3

2

Hz, 1 H, 5'-H) 8.03 (d, J = 8 Hz, 1 H, 8-H) 8.14 (s, 1 H, 5-H) 8.75 (d, J = 5 Hz, 1 H, 3'-H) 9.03 (s, 1 H, 3

3

1-H) 11.94 (br. s, 1 H, OH). – C{ H} NMR (100 MHz, DMSO-d ): δ = 123.0 (C7), 124.1 (C8a), 125.2 13

1

6

(C5), 126.6 (C6'), 128.0 (C8), 136.4 (C6, C5'), 137.1 (C4a), 149.2 (C3'), 149.8 (C1), 154.4 (C1'), 158.1 (C3), 168.7* (derived from HMBC, C=O). 2,3-Dihydro-3-oxo-4-(2-pyridyl)-6-isoquinoline carboxylic acid (2g

). H NMR (500 MHz,

Lactam

1

DMSO-d ): δ 8.83 (ddd, J = 5 Hz , J = 2 Hz, J =1 Hz, 1H, 6'-H), 8.32 (d, J = 6 Hz, 1H, NH), 7.87 3

6

4

5

3

(ddd, J = 8 Hz, J = 8 Hz, J = 2 Hz, 1H, 4'-H), 7.79-7.77 (m, 1H, 7-H), 7.52 (ddd, J = 7 Hz, J = 5 Hz, 3

3

4

3

3

J = 1 Hz, 1H, 5'-H), 7.39 (d, J = 8 Hz, 1H, 8-H), 7.16 (dt, J = 8 Hz, J = 1 Hz, J = 1 Hz, 1H, 3'-H), 7.01

4

3

3

4

5

(d, J = 6 Hz, 1H, 1-H), 6.99 (d, J = 2 Hz, 1H, 5-H). – HRMS (ESI) calcd for C H N O [M + H ]: 3

4

15

11

2

+

3

267.0764; found: 267.0774. 6-Phenyl-4-(2-pyridyl)-3-hydroxyisoquinoline (2h). Chromatography: SiO , CH Cl /MeOH 1% to 2

2

2

10% MeOH. Obtained as green needles (173 mg, 88%). H-NMR (600 MHz, DMSO-d ): δ = 7.38–7.43 1

6

(m, 2 H, 4'-H, 4''-H), 7.45 (t, J = 8 Hz, 2 H, 3''-H, 5''-H), 7.57 (d, J = 8 Hz, 2 H, 2''-H, 6''-H), 7.62 (dd, 3

3

J = 8 Hz, J = 1 Hz, 1 H, 7-H), 7.68 (d, J = 8 Hz, 1 H, 6'-H), 7.73 (br. s, 1 H, 5-H), 7.94 (td, J = 8 Hz,

3

4

3

3

J = 2 Hz, 1 H, 5-H), 8.08 (d, J = 9 Hz, 1 H, 8-H), 8.73–8.77 (m, 1 H, 3'-H), 8.99 (s, 1 H, 1-H), 11.40

4

3

(br. s, 1 H, -OH). – C{ H} NMR (150 MHz, DMSO-d ): δ = 112.5 (C4), 120.5 (C5), 122.2 (C8a, C4''), 13

1

6

122.6 (C7), 127.0 (C2', C6'), 128.2 (C4'), 129.0 (C8), 129.1 (C3'', C5''), 136.4 (C5'), 137.9 (C4a), 139.8 (C1''), 142.3 (C6), 149.1 (C1, C3'), 154.6 (C1'), 158.2 (C3). – HRMS (ESI) Calcd for C H N O [M + 20

15

2

H ]: 299.1179, found: 299.1188. +

6-Methoxy-4-(2-pyridyl)-3-hydroxyisoquinoline (2i). Chromatography: SiO , CH Cl /MeOH 95:5, 2

2

2

Recryst. from 2-PrOH as pale yellow needles (20.2 mg, 8%), mp 233-234 °C. H NMR (600 MHz, 1



Page 12 of 18

DMSO-d ): δ = 3.97 (s, 3H, OCH ), 6.70 (d, J = 8 Hz, 1H, 8-H), 6.96 (d, J = 8 Hz, 1H, 7-H), 7.43–7.34 3

6

3

3

(m, 2H, 6'-H, 5-H), 7.55 (dt, J = 8 Hz, J = 1 Hz, 1H, 5'-H), 7.89 (td, J = 8 Hz, J = 2 Hz, 1H, 4'-H), 3

4

3

4

8.70 (ddd, J = 5 Hz, J = 2 Hz, J = 1 Hz, 1H, 3'-H), 9.02 (s, 1H, 1-H), 11.37 (br. s, 1 H, OH). - C{ H} 3

4

5

13

1

NMR (150 MHz, DMSO-d ): δ = 55.7 (CH ), 101.2 (C8), 112.8 (C8a), 114.9 (C4a), 115.3 (C7), 122.1 6

3

(C6'), 126.5 (C5'), 131.9 (C5), 136.2 (C4'), 139.2 (C4), 143.2 (C1), 149.0 (C3'), 154.9 (C1'), 156.3 (C6), 158.4 (C3). - El. Anal. calcd. (%) for C H N O ´ 0.5 H O (261.3): C 68.95, H 5.02, N 10.72; 15

12

2

2

2

found C 68.65, H 4.64, N 10.57.

Absorption and emission spectra Absorption spectra were recorded in quartz cells (10 mm × 10 mm) on a Varian Cary 100 bio spectrophotometer with baseline correction. Steady state fluorescence spectra were recorded in quartz cells (10 mm × 10 mm) on a Cary Eclipse spectrophotometer at 20 °C. The concentration of the solutions was 10 for absorption spectroscopy and 10 for emission spectroscopy, respectively. The –4

–5

relative fluorescence quantum yields were determined according to standard protocol with Coumarin 33

153 (Φ = 0.38 in EtOH) as reference for measurements in water, MeOH and EtOH and with 34

em

anthracene (Φ = 0.28 in EtOH) as reference for measurements in MeCN, DMSO, DMF, acetone, em

35

CHCl , THF, 1,4-dioxane and EtOAc. 3

Supporting Information Available. Absorption and emissions spectra, spectrometric pH titrations, 1D and 2D NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org.

Notes. The authors declare no competing financial interest.

Acknowledgement. We thank the University of Siegen for financial support. This study was supported by the German Federal Ministry of Education and Research within the EU FP7 project ERA.Net RUSPlus. We thank Mr. Christopher Kuhlmann and Prof. Dr. Carsten Engelhard, University of Siegen, 12 ACS Paragon Plus Environment

Page 13 of 18 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


for mass spectrometric analyses and Mr. Alexander Merker, University of Siegen, for the photographic documentation.

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Mild Synthesis of Fluorosolvatochromic and Acidochromic 3-Hydroxy

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