1 Introduction
Optically active 3-cyclohexen-1-carboxylic acid (CHCA) is a versatile chiral building block for the synthesis of a series of pharmaceuticals and bioactive molecules (Scheme 1a).[1] The resolution of racemic CHCA with chiral amines[2] and the microbial resolution of racemic methyl 3-cyclohexene-1-carboxylate (CHCM) with hydrolases[3] are the most commonly employed approaches for the preparation of this chiral compound (Scheme 1b). In the chiral resolution strategy, discarding at least half of the starting racemic mixture is inevitable. Although it has been reported that the undesired enantiomer can be recycled through esterification followed by racemization, this requires additional steps.[4] Developing more atom-economi- cal and efficient methods for obtaining this enantioenriched unsaturated carboxylic acid can elevate the efficiency and atom economy of synthesizing these pharmaceuticals.
The reported methods of preparing enantiomeric CHCA depend on either the chiral proline-derived oxaborolidine- catalyzed enantioselective Diels-Alder reaction of 1,3-buta- diene with trifluoroethyl acrylate[5] or the titanium-cataly- zed diastereoselective Diels-Alder reaction of 1,3-butadiene with chiral acrylate (Scheme 1b).[6] cis-1,2,3,6-Tetrahydro-naphthalene-1,2-dicarboxylic anhydride is a meso-cyclic anhydride, which can be readily available from the Diels- Alder reaction of 1,3-butadiene with inexpensive maleic anhydride (Scheme 1c). Through the stereoselective methanolysis catalyzed by commercially available esterase from porcine liver (PLE), the desymmetrization of cis-1,2,3,6- tetrahydronaphthalene-1,2-dicarboxylic anhydride to enantiomeric 4-cyclohexene-1,6-dimethanoic acid monomethyl ester can be facilely implemented (Scheme 1c). Thus, we envisaged developing an efficient catalytic system for achieving the decarboxylative synthesis of optically active CHCA with the easily available enantiomeric 4-cyclo- hexene-1,6-dimethanoic acid monomethyl ester under milder conditions. In this work, a catalytic system based on the acridine-derived photocatalyst and the arylthiol as hydrogen-atom transfer (HAT) catalyst was developed for the photo-driven decarboxylative synthesis of enantiomeric CHCA with enantiomeric 4-cyclohexene-1,6-dimethanoic acid monomethyl ester (Scheme 1c).
2 Results and discussion
Firstly, with the stereoselective methanolysis catalyzed by commercially available biocatalyst esterase from porcine liver (PLE),[7] (1S,6R)-4-cyclohexene-1,6-dimethanoic acid monomethyl ester (1a) was prepared conveniently from 1,2,3,6-tetrahydrophthalic anhydride in 99% ee. The enzyme catalyst exhibited higher catalytic efficiency and enantioselectivity than the reported organocatalysts.[8] Unlike iridium or acridinium photocatalysts,[9] adopting acridine in the photo-driven hydrodecarboxylation will not require organic or inorganic base for the pre-generation of carboxylate salts. Then, basis on the selected photosensitizer 9-(2-chlorophenyl)acridine, the selected HAT catalyst 4-fluorothiophenol, and the solvent, the effects of photosensitizer and HAT catalyst loading as well as the substrate concentration on the decarboxylation of 1a were evaluated by the means of design of experiment (DoE). By using the yield of (S)-CHCM as the response indicator, the response surface at the fixed substrate concentration (0.2 mol/L) was established (Figure 1). The analysis of response surface shows that when the loadings of 9-(2-chlorophenyl)acridine and 4-FC6H4SH were 10 mol% and 20 mol% respectively, the highest yield is achieved as 79% yield.
Afterwards, the other condition variables were evaluated (Table 1). By using the photosensitizer 9-(2-chlorophenyl)-acridine and 4-fluorothiophenol in the CH2Cl2 solution under 395-nm violet light irradiation for 24 h at room temperature, (S)-CHCM was obtained in good yield (Table 1, Entry 1). In the absence of water, a marginal decline in yield was observed (Table 1, Entry 2). Meanwhile, adding 1,4-cyclohexadiene (CHD) instead of H2O led to a significant yield decrease (Table 1, Entry 3). We inferred that the presence of trace amounts of water might impose subtle influence on the photoinduced proton-coupled electron transfer (PCET) in the hydrogen bond acridine-carboxylic acid complex. Either replacing CH2Cl2 with other commonly used solvents (Table 1, Entries 4~6) or using 365-nm and 460-nm light sources (Table 1, Entries 7 and 8) failed to further elevate the yield. The activities of 1-propanethiol, phenyl disulfide, 2,4,6-triisopropylben-zenethiol (TRIPSH) and (L)-cysteine were inferior to that of 4-FC6H4SH (Table 1, Entries 9~12). The necessity of oxygen-free atmosphere, photosensitizer, thiol HAT catalyst, and light irradiation has also been verified (Table 1, Entries 13~16).
Table 1 The effects of conditions variation. |
| Entry | Deviation from standard conditionsa | Yieldb/% |
|---|---|---|
| 1 | None | 79 |
| 2 | w/o H2O | 75 |
| 3 | CHD instead of H2O | 27 |
| 4 | MeCN instead of CH2Cl2/H2O | 61 |
| 5 | THF instead of CH2Cl2/H2O | 9 |
| 6 | (CF3)2CHOH instead of CH2Cl2/H2O | <5 |
| 7 | 365 nm instead of 395 nm | 62 |
| 8 | 460 nm instead of 395 nm | 39 |
| 9 | n-PrSH instead of 4-FC6H4SH | 8 |
| 10 | (PhS)2 instead of 4-FC6H4SH | 65 |
| 11 | TRIPSH instead of 4-FC6H4SH | 67 |
| 12 | L-cysteine instead of 4-FC6H4SH | 11 |
| 13 | Open atmosphere | 0 |
| 14 | w/o 9-(2-chlorophenyl)acridine | 0 |
| 15 | w/o 4-FC6H4SH | <5 |
| 16 | w/o light | 0 |
a Reaction conditions: 1a (0.2 mmol, 1.0 equiv.), 9-(2-chlorophenyl)acridine (10 mol%), 4-FC6H4SH (20 mol%), CH2Cl2/H2O (19/1, V/V, 1 mL), r.t., 24 h, 395-nm LEDs (30 W), N2 atmosphere, w/o=without, CHD=1,4-cyclohexadiene. TRIPSH=2,4,6-triisopropylbenzenethiol. b Determined by calibrated gas chromatography (GC) with n-tridecane as the internal standard. |
The acridine photosensitizer is the key factor to the performance of this photo-driven hydrodecarboxylation. The previous investigations have revealed that either 9,10-dihydroacridine or 9-alkyl-10-hydroacridine by-product, stemming from the cross termination of the alkyl radical with acridinyl radical, was formed in the photo-driven decarboxylation of carboxylic acid.[10] When 9-(2-chloro-phenyl)acridine was employed as the photosensitizer for the hydrodecarboxylation of 1a, the cross termination by-product methyl 6-(9-(2-chlorophenyl)-4a,9,9a,10-tetrahy-droacridin-9-yl)cyclohex-3-ene-1-carboxylate was detected by gas chromatography mass spectrometry in the crude product. Meanwhile, the formation·of thiol-ene reaction product between product·(S)-CHCM and 4-FC6H4SH was not detected. Thus, we envision that enlarging the steric hinderance at the C9 position of acridine by introducing bulkier substituent can inhibit the formation of 9,10-dihy-droacridine or 9-alkyl-10-hydroacridine. Thus, a series of 9-substituted acridine photosensitizers were prepared and tested in this hydrodecarboxylative reaction (Scheme 2). The steric hinderances at the 9-position of these acridine photosensitizers were computationally evaluated with the parameter of percent buried volume (VBur/%) at the C9 position. Since H, alkyl, halogen or alkynyl-substitute (2a~2e) have less steric hinderance at the 9-position of acridine than aryl group, their performance in the hydrodecarboxylation of 1a was poor. Besides 9-(2-chloro- phenyl)acridine (2h), more acridines bearing ortho-sub- stituted phenyl group at the 9-position were tested (2g and 2i~2k). All of them exhibited better performance than the less sterically hindered 9-phenyl acridine (2f). Moreover, 9-(2-trifluorome- thylphenyl)acridine (2k) exhibited better performance than 9-(2-chlorophenyl)acridine (2h). More 9-aryl acridines with different substituent at different position (2l~2w) and 12-phenylbenzo[a]acridine (2x) were tested. Overall, the 9-aryl acridines, with the substituent being able to shield the 9-position of acridine, can achieve higher yields (e.g. 2k, 2p and 2q) than the other 9-aryl acridines with less steric hindrance. The correlation between the steric hinderance at the 9-position of acridine photosensitizer (VBur/%) and the yield of decarboxylation product were summarized in Figure 2. It was proposed that the photoinduced PCET took place in the singlet excited state of the hydrogen bond acridine-carboxylic acid complex.[10b] We speculate that the substituent variation on the C9 position of acridine also impose influence on the lowest singlet excited state of the hydrogen bond acridine-car- boxylic acid complex, which leads to the distinct catalytic performance among the acridine photosensitizers with similar Vbur/% values (e.g., 2h/2i vs. 2j/2k). More than acridine-type organic photosensitizers, the other types of organic photosensitizers, including xanthylium, 2,4,6-tri- phenylpyrylium tetrafluoroborate, anthracene-9,10-dicar- bonitrile, acid red 87, fluorescein, 9-mesityl-10-methylacri- dinium tetrafluoroborate, 10-phenyl-10H-phenothiazine and 4CzIPN were also attempted under the base-free conditions, none of them exhibited the performance comparable to 9-(2-trifluoromethylphenyl)acridine photosensitizer. Furthermore, with the tool of flow photo-reactor, the reaction scale for the photo-driven 9-(2-trifluoromethylphenyl)- acridine and 4-fluorothiophenol-catalyzed hydrodecarboxylation of 1a to (S)-CHCM was successfully enlarged from 0.2 mmol to 50 mmol. The enantiomeric excess of the obtained hydrodecarboxylation product was well retained at 99% with a yield of 57%.
Scheme 2 Evaluation of different 9-position substituted acridine-type photocatalystsReaction conditions: 1a (0.2 mmol, 1.0 equiv.), PC (10 mol%), 4-FC6H4SH (20 mol%), CH2Cl2/H2O (V/V=19/1, 1 mL), r.t., 24 h, 30-W 395-nm LEDs, N2 atmosphere. The yields were determined by calibrated GC with n-tridecane as the internal standard. In the parentheses are the values of percent buried volume (VBur/%) at the C9 position of 9-substituted acridine. In the cases of 2t~2v, the VBur/% is the average value of two independent conformers. The VBur/% of independent conformers are given in the square brackets. |
With the optimized conditions in hand, the scope of carboxylic acid was surveyed (Scheme 3). The hydrodecarboxylation of biomass-source long-chain fatty acids, for examples palmitic acid (3a), oleic acid (3b) and linoleic acid (3c) can deliver the alkane or alkene product in good yield. In the cases of 3b and 3c, part of the (Z)-alkene was isomerized to (E)-isomer, but no regio-isomeric alkene was detected by gas chromatography. The protocol can tolerate hydroxyl, carboxylic ester and indole groups (3d~3f). For the hydrodecarboxylation of carboxylic acid bearing bulky α-quaternary carbon (3g), this method was also applicable. Moreover, when this catalytic system was applied in the hydrodecarboxylation of carboxylic acid-containing pharmaceuticals, including Naproxen (3h), Ioxoprofen (3i) and Bezafibrate (3j), the corresponding hydrodecarboxylation products were produced in high yield, which demonstrated the potential utility of this method in the preparation of pharmaceutical analogs.
Scheme 3 Decarboxylative hydrogenation of carboxylic acidsaa Reaction conditions: carboxylic acid 3 (0.2 mmol, 1.0 equiv.), 9-(2-(trifluoromethyl)phenyl)acridine (10 mol%), 4-FC6H4SH (20 mol%), CH2Cl2/H2O (V/ V = 19/1, 1 mL), r.t., 24 h, 395-nm LEDs (30 W), N2 atmosphere. b Determined by calibrated GC with n-tridecane as the internal standard. c Determined by 1H NMR using 1,3,5-trimethoxybenzene as the internal standard |
The Stern-Volmer quenching experiments of the photosensitizer 9-(2-chlorophenyl)acridine with substrate 1a and 4-FC6H4SH were carried out, respectively. The obtained Stern-Volmer plot suggests a more efficient quenching by carboxylic acid 1a than 4-fluorothiophenol (Figure 3a).
Noteworthily, in the beginning of adding quencher 1a into the CH2Cl2 solution of 9-(2-chlorophenyl)acridine, the fluorescence emission intensity was enhanced instead of being diminished, which was reflected on the pattern of I0/I<1 (Figure 3a). With the further addition of quencher 1a, the emission intensity of the system was then suppressed (I0/I>1). This phenomenon suggests the formation of acridine-carboxylic acid hydrogen bond complex[11] with stronger fluorescence emission than 9-(2-chlorophenyl)-acridine. The increase of Stern-Volmer constant (KSV) with the elevation of temperature (Figure 3b) indicates that the fluorescence quenching of the photo-excited acridine photosensitizer by 1a follows a dynamic quenching behavior through the collisions between the emitter and quencher molecules.
Based on the obtained results and the previous investigation on the photocatalytic decarboxylation of carboxylic acid,[10] a reasonable reaction mechanism was proposed (Scheme 4). Firstly, alkylcarboxylic acid interacts with acridine I to form the hydrogen-bonded complex II. The photo-excited II is generated by irradiating complex II with visible light, followed by the generation of acridinyl radical III and carboxyl radical IV via a PCET process. Next, the carboxyl radical quickly eliminates a molecule of carbon dioxide to generate alkyl radical V. Subsequently, the alkyl radical V abstracts the hydrogen atom of arylthiol VI to afford the alkane product and thiyl radical VII. Finally, acridine I and arylthiol VI are regenerated via the PCET between acridinyl radical III and thiyl radical VII.
In summary, an inexpensive noble metal-free photo-catalytic system based on 9-(2-trifluoromethylphenyl)-acridine photosensitizer and 4-fluorothiophenol HAT catalyst was developed for the hydrodecarboxylative synthesis of optically active 3-cyclohexen-1-carboxylic acid, a versatile chiral building block for the synthesis of a series of pharmaceuticals and bioactive molecules. Through experimental and computational investigations, the correlation between the effect of hydrodecarboxylation of 4-cyclohe- xene-1,6-dimethanoic acid monomethyl ester and the steric hindrance at the 9-position of the acridine photosensitizer was revealed.
3 Conclusions
In summary, an inexpensive noble metal-free photo- catalytic system based on 9-(2-trifluoromethylphenyl)-acridine photosensitizer and 4-fluorothiophenol HAT catalyst was developed for the hydrodecarboxylative synthesis of optically active 3-cyclohexen-1-carboxylic acid, a versatile chiral building block for the synthesis of a series of pharmaceuticals and bioactive molecules. Through experimental and computational investigations, the correlation between the effect of hydrodecarboxylation of 4-cyclo-hexene-1,6-dimethanoic acid monomethyl ester and the steric hindrance at the 9-position of the acridine photosensitizer was revealed.
4 Experimental section
4.1 General information
All oxygen- and moisture-sensitive manipulations were carried out under an inert N2 atmosphere using standard Schlenk techniques or glovebox. All reagents were purchased from commercial suppliers without further purification. Anhydrous dichloromethane (CH2Cl2), tetrahydrofuran (THF), acetonitrile (MeCN), hexafluoropropanol (HFIP), 1,2-dimethoxyethane (DME), ethanol, N,N-di- methylformamide (DMF), 2,2,2-trifluoroethanol (TFE), and toluene were purchased from Energy Chemical. The light source was light-emitting diodes matrix, which was purchased from merchant of Fa Guang LEDs on Taobao ecommerce platform. The broadband source was 390 nm-400 nm and the spectral intensity was 30 W. The material of the irradiation vessel was borosilicate glass. The distance from the light source to the irradiation vessel was 2 cm and no lighting filter was used. 1H NMR, 19F NMR, 13C NMR spectra were recorded on Brucker AV-500 (500 MHz for 1H NMR, 471 MHz for 19F NMR, 125 MHz for 13C NMR) and Brucker AV-600 (600 MHz for 1H NMR,565 MHz for 19F NMR,150 MHz for 13C NMR) at ambient temperature with CDCl3 as solvent.. Enantiomeric ratios were determined by chiral HPLC (SHIMADZU LC-20) with n-hexane and iPrOH as solvent. Optical rotation was recorded on a Perkin Elmer 341 polarimeter. Analytical chiral supercritical fluid chromatography (SFC) was performed on the Waters ACQUITY UPC². Chiral SFC was performed using Diacel Chiralpak ID columns (4.6×250 mm×3 μm) and monitored by DAD (diode array detector). Gas chromatography (GC) were detected on Shimadzu GC-2030. A Hitachi RF-6000 fluoresence spectrometer was used to record the emission intensities. All 9-(2-chlo- rophenyl)acridine solutions were excited at 315 nm and the emission intensity at 450 nm was observed. Emission was scanned from 360 nm to 620 nm in 1 nm increments with 6000 nm/min scanning speed. Each experiment is an average of three scans.
4.2 Synthesis of chiral substrate (1S,6R)-6-(meth- oxycarbonyl)cyclohex-3-ene-1-carboxylic acid
According to the reports,[S8] dimethyl cis-4-cyclohexene-1,2-dicarboxylate was synthesized by the acid-catalyzed esterification in anhydrous methanol. HCl (20 mL, 12 mol/L, 2 eqiuv.) was added to a MeOH (200 mL) solution of 1,2,3,6-tetrahydrophthalic anhydride (20.0 g, 131.6 mmol, 1.0 equiv.) and the resulting mixture was refluxed for 3 h. The mixture was then concentrated under reduced pressure and the remaining oil diluted with water (100 mL). Solid NaHCO3 was slowly portionwise added until the pH was neutral. The aqueous phase was extracted with tert-butyl methyl ether (100 mL×4), and the combined organic phases were dried over Na2SO4, filtered and concentrated to give product cis-4-cyclohexene-1,2-dicarbo-xylate as a colorless oily liquid (24.7 g, >95%), which was used to the next step without further purification.
Dimethyl ester cis-4-cyclohexene-1,2-dicarboxylate (10 mmol) was suspended in a 0.1 mol/L dipotassium hydrogen phosphate aqueous solution (20 mL). The pH was then adjusted to 8.5 using 10 mol/L sodium hydroxide. Esterase from porcine liver (activity≥15 U/mg powder, 200 units, 13 mg lyophilized powder, the PLE is a courtesy from Huzhou Yihui Biotechnology Co., Ltd.) was added to the mixture and the pH was kept constant by adding NaOH (1 mol/L). The reaction was stirred at 300 r/min and completed after 6 h. The pH was adjusted to 10 by adding NaOH (1 mol/L) and the obtained slurry was extracted with tert-butyl methyl ether (50 mL×3). The aqueous phase was acidified with HCl until the pH was adjusted to 1, which led to a significant precipitation of the enzyme. To facilitate the extraction, tert-butyl methyl ether (50 mL) was added and the mixture was filtered through a pad of Celite, which was carefully washed with water (10 mL) and tert-butyl methyl ether (10 mL). The aqueous phase was extracted with tert-butyl methyl ether (50 mL×2). The combined organic layers of the second extraction step (under the acidic conditions) were dried over Na2SO4, filtered and concentrated to give compound 1a as an off-white solid (1.7 g, 95% yield, 99% ee). The enantiomeric excess of product of 1a was determined by methyl (1R,6S)-6-(phenylcarbamoyl)-cyclohex-3-ene-1-carboxylate. The chiral product obtained by using the pig liver esterase purchased from Sigma-Aldrich (E3019, lyophilized powder, ≥15 units/mg solid) can deliver the same enantiomeric excess after recrystallizing the product in dichloromethane.
(1S,6R)-6-(methoxycarbonyl)cyclohex-3-ene-1-carboxylic acid: Off-white solid, 1.7 g, 95% yield, 99% ee. $[\alpha ]_{\text{D}}^{\text{25}}$ –140.6 (c 2.0, acetone). 1H NMR (500 MHz, Chloroform-d) δ: 5.72~5.65 (m, 2H), 3.70 (s, 3H), 3.11~3.03 (m, 2H), 2.63~2.53 (m, 2H), 2.42~2.33 (m, 2H). The compound was reported and NMR spectra were consistent with the literature data.[12]
4.3 Methyl (1R,6S)-6-(phenylcarbamoyl)cyclohex-3- ene-1-carboxylate (1a)
To a 50-mL round-bottomed flask was added 1a (184 mg, 1 mmol, 1 equiv.), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (1.2 mmol, 1.2 equiv.) and N,N-dimethylformamide (DMF, 10 mL) were then added. The reaction mixture was stirred at room temperature for 10 h. The reaction was then extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by silica gel flash column chromatography to afford the title compound as a white solid (242.0 mg, 93%).
The carboxylic acid group in 1a was converted into the N-Ph amide for measuring the ee value (99% ee) on the chiral HPLC. HPLC analysis: the ee value was determined using a chiral column OJ-3, n-hexane/i-PrOH (V/V=80/20), flow rate=0.8 mL/min, wavelength=242 nm, temperature=30 ℃, tR(minor)=12.0 min, tR(major)=14.0 min.
4.4 Photocatalytic hydrodecarboxylation to synthesize methyl (S)-cyclohex-3-ene-1-carboxylate ((S)- CHCM)
In a nitrogen filled glove box, a 4-mL vial with a PTFE-coated stir bar was charged with carboxylic acid substrate (0.2 mmol, 1.0 equiv.), 2k (0.02 mmol, 10 mol%) and 4-FC6H4SH (0.04 mmol, 20 mol%), then 950 μL of CH2Cl2 and 50 μL of H2O were added. The reaction mixture was stirred being irradiated within 395-nm LED matrix at room temperature for 12 h. Solvent was concentrated in vacuo. The crude material was purified by silica-gel column chromatography to afford the hydrodecarboxylation products from 1a. Methyl (S)-cyclohex-3-ene-1-carb- oxylate ((S)-CHCM): Colorless oily liquid, 79% yield, 99% ee. $[\alpha ]_{\text{D}}^{\text{25}}$ –112.5 (c 2.0, CHCl3). 1H NMR (600 MHz, Chloroform-d) δ: 5.68 (s, 2H), 3.69 (s, 3H), 2.60~2.54 (m, 1H), 2.28~2.23 (m, 2H), 2.15~2.06 (m, 2H), 2.03~1.98 (m, 1H), 1.73~1.65 (m, 1H). HPLC analysis: the ee value was determined on supercritical fluid chromatography (SFC) using a Diacel Chiralpak ID columns with supercritical carbon dioxide eluent (500 psi), wavelength=220 nm, tR(minor)=1.9 min, tR(major)=2.0 min. The compound was reported and NMR spectra were consistent with the literature data.[12]
Supporting Information Experimental procedures, the synthesis method of the starting materials, and compounds 2c~2e, 2g~2x, 4a~4g characterization data. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn/.
(Lu, Y.)