ES2951005B2 - SYNTHESIS OF HELICAL CARBAZOLES PRESENTING AN IMIDAZOLE RING - Google Patents

Description

DESCRIPTION

SYNTHESIS OF HELICAL CARBAZOLES PRESENTING AN IMIDAZOLE RING

TECHNICAL SECTOR

The present invention falls within the field of organic compound synthesis. More specifically, it relates to a method for synthesizing helical carbazoles containing an imidazole ring that are useful in the production of dyes. Specifically, these compounds emit deep blue luminescence for use in biological detection, organic lasers, and fluorescent probes.

BACKGROUND OF THE INVENTION

Dyes and pigments attract considerable attention due to their use in biological and materials applications. A particularly relevant class of dyes are deep-blue luminescent emitters (Scheme 1), with applications ranging from biological sensing to organic lasers (C. He, H. Guo, Q. Peng, S. Dong and F. Li,J. Mater. Chem. C,2015,3,9942–9947; S. S. Reddy, V. G. Sree, W. Cho and S. H. Jin,Chem. Asian J ,2016, 11, 3275–3282; W. C. Chen, Y. Yuan, S. F. Ni, Z. L. Zhu, J. Zhang, Z. Q. Jiang, L. S. Liao, F. L. Wong and C. S. Lee,ACS Appl. Mater. Interfaces,2017, 9, 7331–7338; J.-H. Lee, C.-H. Chen, P.-H. Lee, H.-Y. Lin, M. Leung, T.-L. Chiu and C.-F. Lin,J. Mater. Chem. C,2019, 7, 5874-5888; H. Min, I. S. Park and T. Yasuda,Angew. Chem. Int. Ed,2021,60,7643-7648).

Diagram 1

Several cyclic compounds incorporating an imidazole ring have demonstrated good electronic and emissive properties in this blue region of light (W. C. Chen, Y. Yuan, S. F. Ni, Q. X. Tong, F. L. Wong and C. S. Lee, Chem. Sci., 2017, 8, 3599-3608; W.-C.

Chen, Z.-L. Zhu and C.-S. Lee,Adv. Opt. Mater.,2018,6,1800258; E. R. Sauvé, C. M. Tonge and Z. M. Hudson,J. Mater. Chem. C,2021, 9, 4164-4172).

On the other hand, the carbazole nucleus is a fundamental type of heterocycle due to the widespread occurrence of this ring in bioactive compounds, advanced materials, and natural products (T.-Y. Shang, L.-H. Lu, Z. Cao, Y. Liu, W.-M. He, B. Yu,Chem. Commun.2019,55,5408-5419; M. Li,Chem. Eur. J.2019, 25, 1142-1151; A. W. Schmidt, K. R. Reddy, H.-J. Knolker,Chem. Rev.2012,112,3193-3328; H. J. Jiang, J. Sun, J. L. Zhang,Curr. Org. Chem.2012,16,2014-2025; J. Roy, A. K. Jana, D. Mal,Tetrahedron2012,68,6099-6121; J. Li, A. G. Grimsdale, Chem. Soc. Rev.2010,39,2399-2410).

Furthermore, helicenes are aromatic polycycles containing fused aromatic rings in an angular arrangement that display enhanced chiroptical properties due to their departure from planarity (A. Urbano and M. C. Carreño, Org. Biomol. Chem., 2013, 11, 699-708; M. Gingras, G. Félix and R. Peresutti, Chem. Soc. Rev., 2013, 42, 1007-1050; T. Mori, Chem. Rev., 2021, 121, 2373-2412).

Consequently, the development of an efficient protocol for the synthesis of compounds incorporating the three previous structures, carbazole helicene and imidazole, is highly desirable for the search for blue emitters and heterocycles with pharmacological properties.

EXPLANATION OF THE INVENTION

The present invention describes imidazoles fused to carbazole azahelicenes, as well as their method of synthesis from readily available 3-iodo-2-formyl indoles. The resulting compounds can be used as deep-blue luminescent emitters.

Diagram 2

Therefore, a first aspect of the invention relates to the compounds of general formula (I) and (II) (hereinafter compounds of the invention) where:

R1 and R2 are the same or different from each other and are selected from the list comprising hydrogen (H), an alkyl group (C<1>-C<8>), an aryl group (C<6>-C<18>) or alkoxy (ORa).

R3 and R4 are the same or different from each other and are selected from the list comprising hydrogen (H), an alkyl group (C<1>-C<8>) or an aryl group (C<6>-C<18>).

R5 is selected from the list comprising hydrogen (H) or an alkyl group (C<1>-C<8>). Both R5 substituents together can form a phenyl or naphthyl ring fused to the ring system to which they are attached.

The term "alkoxy" refers in the present invention to a group of formula -ORa in which Ra is a (C<1>-C<8>) alkyl, such as, but not limited to, methoxy, ethoxy, propoxy or benzyloxy. Preferably the alkoxy is a methoxy.

The term "alkyl" refers in the present invention in the case of R1 and/or R2 and/or R3 to aliphatic chains, linear or branched, having from 1 to 8 carbon atoms; for example, methyl, ethyl, n-propyl, /-propyl, n-butyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl, although preferably they have from 1 to 3 carbon atoms. The alkyl groups may be optionally substituted by one or more substituents such as nitro, hydroxyl, azide, halogen, carboxylic acid or by a group, substituted or unsubstituted, selected from: aryl, hydroxyl, amido, amino, ester, carboxylic acid, ether, thiol, acylamino, carboxamido or nitro. When the alkyl group is substituted by an aryl it is described as "arylalkyl", as, for example, but not limited to, in the case of a benzyl group.

The term "aryl" refers in the present invention to an aromatic carbocyclic chain, having from 6 to 18 carbon atoms, and may be single or multiple rings, in the latter case with separate and/or fused rings. Aryl groups may be optionally substituted by one or more substituents such as alkyl, alkoxy, nitro, hydroxyl, azide, halogen, or carboxylic acid. Mention may be made as examples of aryl groups, and are not limited to, the groups; phenyl, naphthyl, indenyl or anthranyl. Preferably the aryl group is a phenyl.

The term "cycloalkyl" refers in the present invention to a 3- to 12-membered monocyclic or polycyclic aliphatic chain, which is saturated or partially saturated, and which consists only of carbon and hydrogen atoms, such as cyclopropyl, cyclohexyl or norbornyl.

The term "heterocycle" refers in the present invention to a monocyclic or polycyclic chain of 3 to 12 members, which is saturated, partially saturated or unsaturated, and which consists of carbon atoms and at least one heteroatom selected from the group consisting of nitrogen, oxygen, sulfur or selenium. Preferably the heteroatom is nitrogen and the ring is a 5- or 6-membered ring. Examples of heterocycles that may be mentioned, but are not limited to: pyrrole, pyrrolidine, piperidine and indole.

In another preferred embodiment of the compounds of the invention, R2 and R5 are alkyl groups (C<1>-C<8>). More preferably, R2 is hydrogen and/or alkyl and R5 are alkyl groups.

In another preferred embodiment of the compounds of the invention, R2, R5 are alkyl (C<1>-C<8>) or aryl (C<6>-C<18>) groups. More preferably R2 is alkyl. More preferably R2 is methyl.

In another preferred embodiment of the compounds of the invention, R2 is hydrogen.

In a more preferred embodiment, the compounds of the invention are selected from compounds 1, 2, 3, 9, of general formula (I), and compounds 5, 6, 8, 11, of general formula (II). In another preferred embodiment of the invention, the compound derived from imidazoles fused with carbazole azahelicenes is selected from compounds 4, 7 and 10.

The compounds of the present invention represented by formulas (I) and (II) may include isomers, depending on the presence of multiple bonds (e.g.

Z, E), including optical isomers or enantiomers, depending on the presence of chiral centers. Individual isomers, enantiomers, or diastereomers, or mixtures thereof, fall within the scope of the present invention, i.e., the term "isomer" also refers to any mixture of isomers, such as diastereomers, racemic isomers, etc., including their optically active isomers or mixtures in different proportions thereof. Individual enantiomers or diastereomers, as well as their mixtures, can be separated by conventional techniques.

The compounds of the present invention of formula (I), (II), (I’) and (II’) can be obtained or produced by chemical synthesis or generated from natural material of different origin.

Another aspect of the present invention relates to a process for obtaining

the compounds of the invention, their salts and/or solvate thereof, comprising the following steps summarized in Scheme 3:

A) Preparation of carbazoles [general formula (111) and (IV)] by reaction of the indolic terminal alkyne with 3-iodo-2-formyl indoles.

B) Preparation of helical carbazoles (I’) and (N’) by the reaction of iodocarbazoles of general formula (111) and (IV) in the presence of 1,2-diamines and copper catalysis.

The metal-catalyzed synthesis of iodocarbazoles (step A) from an indole butynol has been previously described (Alcaide, B. et al. ACS Catal., 2015, 5, 3417-3421; Martín-Mejías, I. et al. Adv. Synth, Catal., 2021, 363, 1449-1456). Under conventional Sonogashira conditions, the reaction does not stop at non-terminal alkynes and evolves to chromatographically separable iodocarbazoles. Treatment of these fused and functionalized tricycles with a copper-catalyzed formyl indole moiety in the presence of 1,2-diamines was found to result in the formation of helical carbazoles featuring an imidazole ring (step B).

Diagram 3

A third aspect of the invention relates to the compounds of general formula (I) and (II) for use in the preparation of dyes, in particular deep blue luminescent emitters for application in biological detection, in organic lasers and fluorescent probes.

The term "luminescent emitter" as used herein refers to a compound that transforms energy into a luminescent signal.

Another aspect of the invention relates to a deep blue luminescent dye comprising one or more compounds of general formula (I) or one or more compounds of general formula (II). In a preferred embodiment, the dye comprises one or more compounds of formulas 1 to 11, as well as individual enantiomers or diastereomers of the compounds of formulas 1 to 11, or mixtures thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

To complement the description being made and in order to help better understand the characteristics of the invention, a set of figures is attached as part of said description, in which, for illustrative and non-limiting purposes, the following is represented:

Figure 1. Absorption and emission spectra of compounds 5, 9, 10 and 11.

Figure 2. Photophysical properties of compound 9 in different media: dichloromethane (DCM), methanol (MeOH) and heptane (Hept).

Figure 3. Photophysical properties of compound 5 in different media: dichloromethane (DCM), methanol (MeOH) and heptane (Hept).

PREFERRED EMBODIMENT OF THE INVENTION

The invention will now be illustrated by tests carried out by the inventors, which do not, however, limit the scope of the invention.

Example 1

This example refers to the method of preparation of helical helicenes of general formula (I) and (II) from carbazoles (III) and (IV), respectively.

To a solution of carbazole (20 mg, 0.043 mmol) in AcOH/DMF (1:1) (0.52 mL), ortho-aminoaniline (4.8 mg, 0.043 mmol) and a metal catalyst (0.0043 mmol) are added. The reaction mixture is then heated at 100°C in a microwave for 3 hours (TLC). The resulting residue is extracted with AcOEt (3 x 10 mL) and the organic phase is washed with H<2>O (3 x 10 mL) and dried over MgSO<4>. The crude product is purified by column chromatography on silica gel.

Example 2

This example relates to the preparation method of 5,18-Dimethyl-5,18-dihydrobenzo[4’,5’]imidazo[1’,2’:1,6]indolo[3’,2’:4,5]pyrido[3,2-a]carbazole (compound 9).

From 3-(2-iodo-9-methyl-9H-carbazol-1-yl)-1-methyl-1H-indole-2-carbaldehyde (40 mg, 0.086 mol), 24 mg (0.056 mmol, 65%) of the final product are obtained after purification by means of a silica gel chromatography column, using a mixture of n-hexane/AcOEt (3:1) as eluent.

The compound obtained is a whitish-yellow solid. In solution and upon contact with UV radiation, bluish fluorescence emission is observed. Since it is a solid, the melting point was measured. Before melting, the molecule was observed to decompose. The temperature range was 225°C–227°C.

1H NMR (700 MHz, CDCh): 6 = 8.59 (2H, dd,J= 8.40, 3.30 Hz, HAr), 8.55 (1H, d,J= 8.12 Hz, HAr), 8.26 (1H, d,J= 8.33 Hz, HAr), 8.22 (1H, d,J= 7.58 Hz, HAr), 8.14 (1H, d,J= 7.50 Hz, HAr), 7.68 (1H, d,J= 8.01 Hz, HAr), 7.65 (1H, d,J= 8.14 Hz, HAr), 7.61 (2H, dt,J= 10.24, 7.50 Hz, HAr), 7.55 (2H, q,J= 6.83Hz, HAr), 7.40 (2H, dt,J= 60.35, 7.49 Hz, HAr), 4.76 (3H, s, N-CH3), 3.79 (3H, s, N-CH3); 13C NMR (175 MHz, CDCh): 6 = 146.3 (CAr), 144.8 (CAr), 142.2 (C<a>), 140.8 (C<a>), 140.5 (C<a>), 132.3 (C<a>), 131.4 (C<at>), 126.0 (CH<at>), 125.2 (C<at>), 125.1 (CH<a>), 125.0 (C<at>), 124.3 (CH<at>), 124.27 (C<at>), 124.2 (C<at>)123.7 (CH<at>), 122.7 (CH<a>), 122.6 (C<a>), 121.1 (CH<a>), 120.3 (CH<a>), 120.2 (CH<at>X 2), 117.8 (CH<at>), 113.9 (CH<a>), 111.7 (CH<a>), 110.1 (CH<a>), 109.3 (CH<a>), 108.5 (C<a>), 37.2(CH3), 29.7 (CH<3>); HRMS (ES): calcd for C<29>H<20>N<4>[M+H]+: 425.1733; found: 425.1761.

Example 3

This example relates to the preparation method of 9,18-Dimethyl-9,18-dihydrobenzo[4',5']imidazo[1',2':1,6]indolo[3',2':4,5]pyrido[2,3-c]carbazole (compound 5).

Starting from 3-(3-iodo-9-methyl-9H-carbazol-4-yl)-1-methyl-1H-indole-2-carbaldehyde (16 mg, 0.034 mmol), 12 mg (0.028 mmol, 80%) of the final product are obtained, after purification by means of a silica gel chromatography column, using a mixture of n-hexane/AcOEt (3:1) as eluent. The compound obtained is a whitish yellow solid. Fluorescence is also observed in this isomer in solution upon contact with UV radiation. The observed colour has a more violet tone than the previous compound.

Since it is a solid, the melting point is measured. Before melting, the molecule is observed to decompose. The temperature range was 229°C–231°C.

1H NMR (700 MHz, CDCh): 6 = 8.84 (1H, d,J= 8.99 Hz, HAr), 8.56 (1H, dd,J= 7.57, 1.45 Hz, HAr), 8.11 (1H, m, HAr), 7.98 (1H, m, HAr), 7.85 (1H, d,J= 8.25 Hz, HAr), 7.69 (2H, m, HAr), 7.54 (5H, m, HAr), 7.18 (2H, m, HAr), 4.80 (3H, s, N-CH3), 4.07 (3H, s, N-CH3); 13C NMR (175 MHz, CDCh): 6 = 144.8 (C<a>), 142.0 (C<a>), 141.3 (C<at>), 140.8 (C<a>), 138.9 (C<at>), 131.4 (C<at>), 127.6 (C<a>), 127.1 (C<at>), 126.2 (CH<at>), 125.9 (CH<at>), 125.4 (CH<at>), 124.7 (CH<at>), 123.9 (CH<a>), 123.5 (C<at>), 123.4 (C<at>), 122.3 (CH<at>), 120.3 (CH<a>), 119.2 (CH<at>), 117.7 (CH<at>), 117.1 (C<at>), 115.7 (C<at>), 113.9 (C<a>), 113.8 (CH<at>x 2), 109.7 (CH<a>), 108.3 (CH<at>), 106.5 (CH<a>), 32.3 (CH<3>), 29.5 (CH<3>). HRMS (ES): calcd for C<29>H<20>N<4>[M+H]+: 425.1761; found: 425.1753.

Example 4

This example relates to the preparation method of 3-Methoxy-5,18-dimethyl-5,18-dihydrobenzo[4',5']imidazo[1',2':1,6]indolo[3',2':4,5]pyrido[3,2-a]carbazole (compound 10).

Starting from 3-(2-iodo-9-methyl-9H-carbazol-1-yl)-6-methoxy-1-methyl-1-indole-2-carbaldehyde (23 mg, 0.046 mmol), 11 mg (0.024 mmol, 52%) of the product are obtained after purification by means of a silica gel chromatography column using a n-hexane/AcOEt (2:1) mixture as eluent. The compound obtained is a whitish-yellow solid, which decomposes before melting.

1H NMR (700 MHz, CDCh): 6 = 8.59 (1H, d,J =8.4 Hz, H<at>), 8.57(1H, d,J =8.2 Hz, HAr)

8.23 (1H, d,J= 8.4 Hz, H<at>), 8.21 (1H, d,J= 7.4 Hz, H<at>), 8.10 (1H, dd,J= 8.0, 1.2 Hz,

H<at>), 8.07 (1H, d,J= 2.4 Hz, H<at>), 7.63 (1H, d,J= 7.9 Hz, H<at>), 7.58 (2H, m, H<at>), 7.42

(1H, t,J= 7.3 Hz, H<at>), 7.19 (2H, dd,J= 8.8, 2.5 Hz, H<at>), 4.72 (3H, s, OCH<3>), 3.92 (3H,

s, NCH<3>), 3.77 (3H, s, NCH<3>); 13C NMR (175 MHz, CDCI<3>): 6 = 154.2 (C<at>), 146.8 (C<at>),

144.8 (C<at>), 142.3 (C<at>), 140.9 (C<at>), 135.8 (C<at>), 132.2 (C 10 1.5 (C<at>), 126.4 (C<at>), 126.0 (CH<at>), 125.4 (C<at>), 124.4 (C<at>), 124.1 (CH<at>), 122.8 (C<at>), 122.6 (CH<at>), 121.2

(CH<at>), 120.2 (CH<at>x 2), 117.5 (CH<at>), 115.6 (CH<at>), 113.9 (CH<at>), 112.2 (C<at>), 111.6

(CH<at>), 110.8 (CH<at>), 109.5 (CH<at>), 108.8 (C<at>), 105.1 (CH<at>), 55.8 (CH<3>), 37.3 (CH<3>), 32.3

(CH<3>). HRMS (ES): calcd for C<30>H<22>N<4>O [M+H]+: 455.1866; found: 455.1864.

Example 5

This example relates to the preparation method of 15-Methoxy-9,18-dimethyl-9,18-dihydrobenzo[4',5']imidazo[1',2':1,6]indolo[3',2':4,5]pyrido[2,3-c]carbazole (compound 11).

From 3-(3-iodo-9-methyl-9H-carbazol-4-yl)-5-methoxy-1-methyl-1H-indole-2-carbaldehyde (9 mg, 0.018 mmol), purifying by column chromatography

of silica gel using as eluent a mixture of n-hexane/AcOEt (2:1),

They obtain 3 mg (0.007 mmol, 39%) of the final product.

The compound obtained is a whitish yellow solid, which decomposes before

melt.

1H NMR (700 MHz, CDCh): 6 = 8.83 (1H, d,J= 8.6 Hz, HAr), 8.55 (1H, d,J= 8.3 Hz,

HAr), 8.13 (1H, d,J= 7.9 Hz, HAr), 7.97 (1H, d,J= 7.8 Hz, HAr), 7.68 (1H, d,J= 8.7

Hz, HAr), 7.58-7.50 (5H, m, HAr), 7.24-7.18 (3H, m, HAr), 4.76 (3H, s, OCH<3>), 4.07 (3H,

s, CH3), 3.54 (3H, s, CH3); 13C NMR (175 MHz, CDCh): 6 = 153.3 (C<at>), 144.3 (C<at>),

141.7 (C<at>), 141.6 (C<at>), 141.3 (C<at>), 138.9 (C<at>), 135.9 (C<at>), 131.3 (C<at>), 127.5 (C<at>),

126.8 (CAr), 126.6 (CHAr), 125.4 (CH<at>), 123.9 (CH<at>), 123.5 (C<at>), 123.3 (C<at>), 122.4 (CHAr), 120.1 (CH<at>), 117.6 (CH<at>), 116.7 (C<at>), 115.9 (CH<at>), 115.8 (C<at>), 113.8 (CH<at>), 113.7 (CH<at>), 110.6 (CH<at>), 108.2 (CH<at>), 107.3 (CH<at>), 106.2 (CH<at>), 55.3 (CH<3>), 32.5 (CH<3>), 29.5 (CH<3>); HRMS (ES): calcd for C<30>H<22>N<4>O [M+H]+: 455.1866; found: 455.1869.

Example 6

This example shows the photophysical properties of compounds 5, 9, 10 and 11, obtained according to the present invention.

Table 1 shows the photophysical properties determined for compounds 5, 9, 10, and 11 in different solvents. Initially, dichloromethane was chosen as the solvent in which the compounds dissolve best.

Table 1

The fluorescence quantum yield (f) is calculated at an excitation wavelength of 368 nm using 9-10-diphenyltantracene as a reference standard (^fl (cyclohexane) = 0.9).

The two helical carbazoles presenting an imidazole ring with all its substituents hydrogen (compounds 5 and 9) present a very similar absorption profile, but with a slight bathochromic shift (ca. 26 nm) of compound 5 with respect to compound 9 and presenting a very similar absorptivity in both cases (Figure 1). The presence of the methoxyl activating group (compounds 10 and 11) causes the absorptivity to increase with respect to the absorptivity of its peers and, only in the case of compound 11, a slight hypsochromic shift (ca. 6 nm) of its absorption peaks is observed.

With respect to their emissive properties, the emission spectra of compounds 9 and 10 present two undifferentiated bands with a maximum located at 415 and 426 nm, respectively, and high fluorescence quantum yields (f) (0.58 and 0.44, respectively). Meanwhile, compounds 5 and 11 present a more defined emission profile, with two bands and a shoulder (ca. 430, 456 and 486 for compound 5) and with very similar quantum yields (0.38 and 0.36, respectively), as observed in Figure 1.

When performing tests with other solvents, such as methanol (polar protic solvent) and heptane (non-polar solvent), it is concluded, as can be seen in Figures 2 and 3, that the nature of the solvent does not greatly affect the photophysical properties of the compounds.

Claims (12)

CLAIMS 1. Compounds derived from imidazoles fused with carbazole azahelicenes of general formula (I) and (II) where: R1 and R2 are the same or different from each other and are selected from the list comprising hydrogen (H), a (C<1>-C<8>) alkyl group, a (C<6>-C<18>) aryl group, or alkoxy (OR<a>) where R<a> is a (C<1>-C<8>) alkyl group, R3 and R4 are the same or different from each other and are selected from the list comprising hydrogen (H), a (C<1>-C<8>) alkyl group, or a (C<6>-C<18>) aryl group, R5 is selected from the list comprising hydrogen (H) or a (C<1>-C<8>) alkyl group. Both R5 substituents together can form a phenyl or naphthyl ring fused to the ring system to which they are attached. 2. Compounds, according to claim 1, of general formula (I) where the compound is selected from among the compounds of formula 1, 2, 3 and 9. 3. Compounds, according to claim 1, of general formula (II) where the compound is selected from among the compounds of formula 5, 6, 8 and 11. 4. Compound derived from imidazoles fused with carbazole azahelicenes of formula 4. 5. Compound derived from imidazoles fused with carbazole azahelicenes of formula 7. 6. Compound derived from imidazoles fused with carbazole azahelicenes of formula 10. 7. Process for the synthesis of compounds derived from imidazoles fused to carbazole azahelicenes from 3-iodo-2-formyl indoles, characterized by the following steps: A) Preparation of the carbazoles by reaction of the indole terminal alkyne with 3-iodo-2-formyl indoles. B) Preparation of the helical carbazoles by the reaction of iodocarbazoles in the presence of 1,2-diamines under copper catalysis. 8. Method for synthesizing the compounds of general formula (I) and (II), according to claim 7, wherein the diamine is ortho-aminoaniline. 9. Deep blue luminescent emitting dye comprising one or more claimed compounds of general formula (I). 10. Deep blue luminescent dye comprising one or more claimed compounds of general formula (II). 11. Deep blue luminescent dye comprising one or more of the claimed compounds of formula 1 to 11. 12. Deep blue luminescent emitting dye comprising optical isomers or individual enantiomers or diastereomers of the claimed compounds or mixtures thereof.