Synthesis and Structural Properties of Axially Chiral Binaphthothiophene Dicarboxylic Acid

Abstract

Axially chiral binaphthothiophene dicarboxylic acid was prepared as a novel functionalized chiral dicarboxylic acid. The crystal structures of both the racemic form and its salt with chiral diamine revealed the intramolecular S···O interactions (chalcogen bonds) between the sulfur in the naphthothiophene rings and the oxygen of the carboxy groups. The negative–positive and the positive–negative Cotton effects from longer to shorter wavelengths were observed for (R)- and (S)-enantiomers, respectively, in the circular dichroism (CD) spectra.

Axially chiral biaryl dicarboxylic acids such as 1,1′-binaphthyl 2,2′-dicarboxylic acid (1) and their derivatives have attracted considerable attention as chiral organocatalysts^1–12) and chiral ligands^13,14) in asymmetric synthesis. Although they have prominent utility in organic synthesis, structural variation of this class of molecules is not necessarily abundant. Therefore, the development of axially chiral biaryl carboxylic acids possessing novel structural properties would have a significant impact on stereoselective chemical transformations.

We have been working on the synthetic study of axially chiral amino acids having aniline-type amino groups and their related molecules including the derivatives of 1.^15–18) During the course of this study, we were interested in the axially chiral binaphthothiophene dicarboxylic acid 2, which possesses sulfur atoms in the fused tricyclic π-systems, and could be expected to be a pivotal functional group for molecular recognition through a chalcogen bond.^19–24) We were also interested in constructing a wider chiral environment than that of the axially chiral benzothiophene dicarboxylic acid 3,²⁵⁾ which is narrow due to its smaller fused π-system (Fig. 1). Herein, synthesis, optical resolution, structural features, and circular dichroism (CD) spectra of 2 were described.

Fig. 1. Axially Chiral Dicarboxylic Acids

We began the synthesis of 2 from Ullmann coupling of 4, which was prepared according to the reported procedure²⁶⁾ (Chart 1). This Ullmann coupling employed similar conditions, which were applied for 3,²⁵⁾ worked well to give dimethyl ester (dl)-5 in a 53% yield. The ester hydrolysis of 5 gave the desired 2 in racemic form. With a survey of the conditions for optical resolution of 2, fractional crystallization of the salts with chiral diamine 6, which was employed for optical resolution of racemic 1, was found to be effective.²⁷⁾ Upon treatment of racemic 2 with 0.5 eq of (S,S)-6 in acetone, the salts of 2 and (S,S)-6 were precipitated. After removing (S,S)-6 from the salts by acidification, optically active dicarboxylic acid 2 was obtained in >99% enantiomeric excess (ee).

Chart 1. Preparation of (S)-2

The absolute configuration of 2 obtained with (S,S)-6 was determined to be S by X-ray analysis of the salt as shown in Fig. 2A. This analysis indicated that (S)-2 and 6 were assembled in a 1 : 1 ratio via the hydrogen bonds between the ammonium groups of 6 and one of the carboxylate groups of (S)-2 (N–O distances in the hydrogen bonds: 2.904(3) and 2.720(3) Å). Furthermore, X-ray analysis of the single crystal of racemic 2 was carried out. As shown in Fig. 2B, (R)-2 and (S)-2 were associated in a 1 : 1 ratio through the hydrogen bonds between the carboxy groups of each of the enantiomers (O–O distances in the hydrogen bonds: 2.588(2) and 2.611(2) Å). It was also revealed that the naphthothiphene rings were twisted in a nearly perpendicular geometry around the chiral axis with dihedral angles of 87.8(3)° (ϕa,b–c,d) in the optically active form (Fig. 2A), as well as –80.2(3)° (ϕa,b–c,d) and 83.1(3)° (ϕa′,b′–c′,d′) in the racemic form (Fig. 2B).

Fig. 2. Crystal Structures of (S)-2·(S,S)-6 Complex (A) and Racemic 2 (B) (60% Probability)

Hydrogen atoms are omitted for clarity except for the ones on the stereogenic centers of 6.

It is noteworthy that short contacts between the sulfur in the fused aromatic rings and the oxygen of the carboxylate groups were observed. The distances between the oxygen and sulfur atoms are 2.997(2) Å and 2.897(2) Å, in the optically active form (Fig. 2A) and 2.910(2), 2.849(2), 2.810(2), and 2.921(2) Å in the racemic forms (Fig. 2B). All of the distances shorter than the sum of the van der Waals radii of sulfur and oxygen atoms (3.32 Å) indicated formation of a chalcogen bond in an intramolecular fashion.²⁸⁾

The carboxy groups and the π-faces of the naphthothiophene rings seem to be almost in the same plane without any remarkable twist around the C–C bonds of the carboxy groups and naphthothiophene groups. The dihedral angles of each S–C–C–O are −18.7(3)° and −3.5(3)° in the optically active form (Fig. 2A), and −18.7(2)°, 6.6(2)°, −3.4(2)°, and 15.8(2)° in the enantiomers of the racemic crystal (Fig. 2B). These co-planar arrangements suggest that the conformation around the C–C bonds of the carboxy groups and naphthothiophene rings are locked by the intramolecular S···O interactions.^20,24) This is one of the most characteristic structural features of 2.

For investigating the chiroptical properties of 2, the CD spectra of (R)-2 and (S)-2 were measured in acetonitrile (Fig. 3). (R)-2 showed the negative–positive Cotton effect from longer to shorter wavelengths in the CD spectrum. On the other hand, (S)-2 showed the positive–negative Cotton effect from longer to shorter wavelengths. These spectra suggest that these couplet Cotton effects were derived from the negative and the positive twist of the long axis of the naphthothiophene chromophores for the R and S isomers, respectively. This appearance of a couplet Cotton effect is similar to those observed in binaphthyl-type axially chiral compounds including 1.²⁹⁾

Fig. 3. UV and CD Spectra of (R)-2 and (S)-2 in CH₃CN

In conclusion, the preparation and optical resolution of axially chiral binaphthothiophene dicarboxylic acid 2 was achieved. Intramolecular S···O interactions were observed and found to be key for the conformation lock between the carboxy groups and the naphthothiophene rings. Investigation of the characteristic functions of 2 as a chiral organocatalyst as well as a ligand by virtue of the intramolecular chalcogen bond is currently underway.

Experimental

General Methods

Melting points were measured by using a Yanagimoto micro melting point apparatus and were uncorrected. NMR spectra were obtained with a JEOL ECX-400 PKT Spectrometer or a JEOL ECA-600 Spectrometer, with chemical shift being given in ppm units (¹H-NMR in CDCl₃–CHCl₃ as internal standards, indicating 7.26, tetramethylsilane as internal standards, indicating 0; ¹³C-NMR in CDCl₃–CDCl₃ as internal standards, indicating 77.16; ¹H-NMR in acetone-d₆: acetone as internal standards, indicating 2.05; ¹³C-NMR in acetone-d₆: acetone-d₆ as internal standards, indicating 29.84, 206.26). Spin–spin coupling constants were given in Hz units. IR spectra were recorded with a JASCO FT-IR 4200 Spectrometer. High resolution (HR)-MS was recorded with a Bruker Daltonics impact HD-KC (for electrospray ionization (ESI)). Specific rotation was measured with a JASCO P-2200 Polarimeter. UV/Vis and CD spectra were recorded with a JASCO V-550 UV/VIS Spectrophotomer and a JASCO J-720W Spectropolarimeter, respectively.

Silica gel column chromatography was carried out by using Silica gel 60 N (spherical, neutral, 63–210 µm, Kanto Chemical Co., Inc.). TLC analysis and PTLC were performed on commercial glass plates bearing a 0.25 mm layer and a 0.5 mm layer of Merck Kiesel-gel 60 F₂₅₄, respectively. Analytical HPLC was run with a JASCO PU-2089 Plus instrument, equipped with a Daicel CHIRALCEL OD-H (4.6×250 mm), and a JASCO UV-2075 Plus UV/Vis detector (detection: 254 or 216 nm).

All chemicals and reagents were commercially purchased and used without further purification.

Synthetic Procedures

Dimethyl [1,1′-Binaphtho[2,1-b]thiophene]-2,2′-dicarboxylate ((dl)-5)

A solution of methyl 1-chloronaphtho[2,1-b]thiophene-2-carboxylate (4)³ (50 mg, 0.18 mmol) and activated Cu (46 mg, 0.72 mmol, 4.0 equiv.) in N,N-dimethylformamide (DMF) (1.0 mL) was refluxed under Ar atmosphere for 24 h. After the reaction mixture was cooled to room temperature (r.t.), the mixture was added H₂O and extracted with AcOEt. The organic layer was washed with brine, dried over Na₂SO₄, filtered, and evaporated to give a residue. The residue was purified by the prep. TLC (SiO₂, hexane–AcOEt=2 : 1 to afford (dl)-5 (23 mg, 53%).

Yellow solid: mp 252–254°C. ¹H-NMR (600 MHz, CDCl₃) δ: 3.61 (6H, s), 7.00–7.08 (2H, m), 7.30–7.35 (4H, m), 7.86 (2H, d, J=7.6 Hz), 7.91 (2H, d, J=8.9 Hz), 7.99 (2H, d, J=8.9 Hz). ¹³C-NMR (150 MHz, CDCl₃) δ: 52.3, 120.8, 122.7, 125.7, 127.4, 128.0, 129.1, 129.3, 130.7, 132.1, 133.6, 140.6, 140.7, 162.3. IR (KBr) cm⁻¹: 1720, 1482, 1436, 1318, 1233, 1102, 1071, 910, 807, 730 cm⁻¹. HR-ESI-MS m/z: 505.0537 [M+Na]⁺ (Calcd for C₂₈H₁₈NaO₄S₂: 505.0539).

[1,1′-Binaphtho[2,1-b]thiophene]-2,2′-dicarboxylic Acid ((dl)-2)

To a solution of (dl)-5 (439 mg, 0.97 mmol) in tetrahydrofuran (THF)–MeOH (2 : 1, 10 mL), 2 N aq. NaOH (3 mL) was added at r.t. After being refluxed for 21 h, the reaction mixture was cooled to r.t., and washed with Et₂O. The aqueous layer was acidified with 2 N aq. HCl, and extracted with AcOEt. The organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to give (dl)-2 (298 mg, 72%).

Crystallographic Data for the Single Crystal of (dl)-2·2i-PrOH Obtained by Recrystallization from i-PrOH

C₂₆H₁₄O₄S₂·2(C₃H₈O), M=574.68, 0.25×0.10×0.07 mm³, Monoclinic, P2₁ (#4), a=10.8762(2), b=17.7570(3), c=15.4464(2) Å, α=90.00°, β=104.9560(10)°, γ=90.00°, V=2882.09(8) ų, Z=4, ρ_calcd=1.324 g cm⁻³, T=103(2) K, 63763 reflections measured, 12472 unique. The final R₁ and wR were 0.0396 and 0.0794 (all data). These data have been deposited with the Cambridge Crystallographic Data Center as CCDC 1863131.

Optical Resolution of 2

Racemic 2 (2.6 g, 5.7 mmol, 1.0 equiv.) was dissolved with acetone (300 mL) at r.t. To the solution, a solution of (1S,2S)-1,2-diphenylethane-1,2-diamine ((S,S)-6) (607 mg, 2.9 mmol, 0.5 eq) in acetone (15 mL) was added at rt. After being stirred for 13 h at r.t., the solids were collected, and washed with acetone. The solids were dissolved in acetone and 2 N aq. HCl, and the solution was then extracted with AcOEt. The organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to give a residue. The residue was dissolved with CHCl₃ under heating conditions, then cooled to r.t. to give the solids. The solids were washed with CHCl₃–hexane (1 : 9), and dried in vacuo at 60°C to give (S)-2 (988 mg, 38%, >99% ee).

(R)-2 was also obtained from (dl)-2 under the same conditions except for employing chiral amine (R,R)-6 instead. The ee of (R)-2 and (S)-2 were determined by HPLC analysis with chiral stationary phase as shown in the Supporting Information.

(R)-2

[α]_D²⁰ +38.2 (c=0.5, MeOH, >99% ee). CD λ_ext (CH₃CN) nm (Δε): 347 (−2.93), 324 (8.34), 265 (12.23), 245 (−72.90), 229 (82.87). UV λ_max (CH₃CN) nm (log ε): 316 (4.31), 234 (4.62).

(S)-2

[α]_D²⁰ −41.1 (c=0.5, MeOH, >99% ee). CD λ_ext (CH₃CN) nm (Δε): 347 (2.85), 323 (−8.35), 265 (−11.98), 244 (73.97), 229 (−82.47).

The following analytical data were obtained with (S)-2: Yellow solid. mp 270–271°C. ¹H-NMR (600 MHz, acetone-d₆) δ: 7.02–7.11 (2H, m), 7.32–7.39 (4H, m), 7.95–8.00 (2H, m), 8.03–8.06 (2H, m), 8.20 (2H, d, J=8.9 Hz) 11.37 (2H, br s). ¹³C-NMR (150 MHz, acetone-d₆) δ: 121.8, 123.1, 126.6, 127.9, 129.9, 130.1, 130.3, 131.5, 133.0, 134.6, 141.1, 141.5, 163.1. IR (KBr) cm⁻¹: 3055, 1685, 1482, 1433, 1263, 806, 773, 742, 702. HR-ESI-MS m/z: 477.0230 [M+Na]⁺ (Calcd for C₂₆H₁₄NaO₄S₂: 477.0226).

Crystallographic data for the single crystal of (S)-2·(S,S)-6·EtOH·H₂O obtained by recrystallization from EtOH: C₂₆H₁₂O₄S₂·C₁₄H₁₈N₂·C₂H₆O·H₂O, M=730.86, 0.25×0.07×0.04 mm³, Orthorhombic, P2₁2₁2₁ (#19), a=9.69750(10), b=17.4301(2), c=21.9385(3) Å, α=90.00°, β=90.00°, γ=90.00°, V=3708.23(8) ų, Z=4, ρ_calcd=1.309 g cm⁻³, T=103(2) K, 92197 reflections measured, 10427 unique. The final R₁ and wR were 0.0395 and 0.0790 (all data). These data have been deposited with the Cambridge Crystallographic Data Center as CCDC 1863136.

Acknowledgments

This work was supported by a Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

The online version of this article contains supplementary materials.

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