Synthesis of 2-[(3,4,5-Triphenyl)phenyl]acetic Acid and Derivatives

Abstract

New phenylacetic acid derivatives with potentially valuable biological activities and the ability to act as starting materials for various functionalizations have been prepared by a multi-step synthesis. Starting from 2,6-dibromo-4-methylaniline, the synthetic route involves the construction of the basic aromatic structure (3,4,5-triphenyltoluene) (two steps), followed by its conversion into 2-[(3,4,5-triphenyl)phenyl]acetic acid and derivatives (up to five steps). Based on this multi-step synthesis, five compounds not previously reported in the literature were synthesized; the literature-known 3,4,5-triphenyltoluene was synthesized for the first time in the manner described. This synthesis is applicable for the preparation of numerous new representatives of this class of compounds.

1. Introduction

Phenylacetic acid and its derivatives represent a versatile class of substances [1,2,3,4] with a broad spectrum of biological activities. Phenylacetic acid alone is a plant auxin, but also has anti-microbial activities. As it occurs very frequently in nature, its role in plants, fungi, and bacteria has been studied intensively [1,2,3].

Phenylacetic acid derivatives, as well as phenylacetic acid itself, play an important role as metabolites [5,6,7,8,9]. An example of this is 3,4-dihydroxyphenylacetic acid (Figure 1a), which is said to have anti-cancer properties [9]. This phenylacetic acid derivative is a metabolite of the neurotransmitter dopamine [6], but has also been identified as a metabolite of other compounds such as rutin [8], a flavonoid with a very broad pharmacological spectrum of activity [10,11].

It is also worth mentioning that phenylacetic acid possesses ammonium ion-binding activity and is used as an adjunct in the treatment of acute hyperammonemia and associated encephalopathy in patients with urea cycle enzyme deficiencies [12]. Moreover, sodium phenylacetate was found to affect the growth and differentiation of tumor cells [13]. Various derivatives, such as 4’-carboxymethyl-4-nonyloxy-[1,1′-biphenyl]-3-carboxylic acid (BPDA2) and 2-[(1,1′-biphenyl)-4-yl]-N-(3-fluorobenzyl)acetamide (see Figure 1b), were reported to have antiproliferative and antitumor properties against various types of cancer [14,15,16,17]. In addition, 2-[(3,5-diphenyl)phenyl]acetic acid and derivatives have been proposed as candidates for the treatment of Alzheimer’s disease [18].

Interestingly, phenylacetic acid is a building block of many drugs, including ibuprofen, diclofenac, and flurbiprofen (see Figure 1c). Ester and amide derivatives of phenylacetic acid are also used as medicines, such as cyclopentolate and atenolol, respectively (Figure 1d). The phenylacetamido group is also an important subunit of other drug molecules, such as penicillin G (Figure 1d). The above-mentioned pharmaceuticals are used in a variety of ways, e.g., as non-steroidal anti-inflammatory agents, analgesics, anti-cancer agents, mydriatics, and cycloplegics, as well as others.

Phenylacetic acid and its derivatives also play a very important role as starting materials for the synthesis of numerous drugs, for example bendazol, camylofin, triafungin, phenacenide, lorcainide, phenindione, and cyclopentolate; it is also used in the production of penicillin.

Due to the interesting properties of phenylacetic acid derivatives and the possibility of their broad application, both the development of practical synthetic routes and the synthesis of new derivatives are of great importance. This article describes the synthesis of new phenylacetic acid derivatives (compounds 1a, 1b and 2; Figure 2) with potentially interesting biological activity.

2. Results and Discussion

The basic aromatic structure (3,4,5-triphenyltoluene) was constructed from commercially available compounds. First, 2,6-dibromo-4-methylaniline (3) was diazotized with tert-butyl nitrite and reacted with CuBr₂ in a Sandmeyer reaction to give 3,4,5-tribromotoluene (4) (Scheme 1) [19]. The brominated positions were then subjected to phenylboronic acid under classical Suzuki–Miyaura coupling conditions [20] to introduce the phenyl rings. The literature-known 3,4,5-triphenyltoluene (5) was synthesized in this way for the first time and was obtained with a yield of 68%. The synthesis of 3,4,5-triphenyltoluene, published last year [21], involves the use of 3,4,5-triphenylphenol, which was obtained as a representative of the class of 3,4,5-trisubstituted phenols by a Rh(III)-catalyzed coupling of phosphonium cations with internal alkynes. It should be mentioned that our procedure was carried out on a much larger scale than that described in the literature.

Compound 5 was then functionalized to 3,4,5-triphenylbenzyl bromide (6) using N-bromosuccinimide (NBS) and azobisisobutyronitrile (AIBN) as a radical initiator [22] (Scheme 2).

Although procedures for the one-step conversion of benzyl bromides to the corresponding phenylacetic acid are described in the literature [23], the conventional route via a Kolbe nitrile synthesis [24] and subsequent hydrolysis was chosen in the case of compound 6, as the intermediate products 2-[(3,4,5-triphenyl)phenyl]acetonitrile (7), and in particular 2-[(3,4,5-triphenyl)phenyl]acetamide (2), are of interest to our research.

The conversion of 3,4,5-triphenylbenzyl bromide (6) into 2-[(3,4,5-triphenyl)phenyl]acetonitrile (7) was achieved by reaction with potassium cyanide in the presence of 18-crown-6 in acetonitrile. In order to achieve an acceptable conversion rate, a comparatively large amount of 18-crown-6 had to be used; the best ratio determined was 3 to 4 eq. educt per eq. crown ether.

The subsequent hydrolysis of compound 7 was tested under both alkaline (potassium hydroxide) [25] and acidic (hydrogen bromide in acetic acid) [26] conditions. The performed experiments showed that the reaction in the acidic medium was more effective than the alkaline one in order to obtain the desired products. In this way, 2-[(3,4,5-triphenyl)phenyl]acetamide (2) could be obtained with a yield of 71% and its conversion to 2-[(3,4,5-triphenyl)phenyl]acetic acid (1a) was achieved with a yield of 85% by treatment with aqueous HCl and a catalytic amount of TiCl₄. The Ti(IV) catalyzed hydrolysis reaction in the presence of aqueous HCl [27] allows a conversion of primary amides to carboxylic acids under mild conditions. By treating 1a with potassium hydroxide, potassium 2-[(3,4,5-triphenyl)phenyl]acetate (1b) was prepared.

It should be noted that all reaction steps and all plausible alternatives from the literature are very difficult to perform due to the poor solubility of the compounds in polar media caused by the large aromatic backbone.

3. Conclusions

A multi-step synthesis has been developed for the preparation of 2-[(3,4,5-triphenyl)phenyl]acetic acid and derivatives with potentially valuable biological activities. Investigations into the effect of the aromatic rings in the 3,4,5 positions on the properties of the new phenylacetic acid derivatives are in progress. On the basis of this multi-step synthesis, five compounds not previously reported in the literature were synthesized (compounds 1a, 1b, 2, 6 and 7); compound 5 was prepared for the first time in the manner described. It should be noted that the multi-step synthesis of the target compounds required only one chromatographic separation (purification of compound 7), and the remaining compounds were purified by recrystallization. The described synthetic route has the potential to be further optimized and is also applicable for the preparation of a wide range of new representatives of this class of compounds. In addition, the prepared compounds are valuable starting materials for various functionalization reactions.

4. Materials and Methods

The starting materials 2,6-dibromo-4-methylaniline and phenylboronic acid are commercially available and were purchased from Sigma-Aldrich (St. Louis, MO, USA). 3,4,5-tribromotoluene (4) was prepared according to the procedure reported in the literature [19]. Analytical TLC was carried out on silica gel 60 F₂₅₄ plates and column chromatography was carried out on silica gel. Melting points were measured on a hot stage microscope Büchi 510 (Büchi, Flawil, Switzerland) and were uncorrected. ¹H and ¹³C NMR spectra were recorded on a Avance III-500 MHz spectrometer (Bruker, Billerica, MA, USA) using Me₄Si as internal standard and are given in Supporting Information. FT-IR spectra were obtained from a Nicolet iS10 FT-IR spectrometer (Thermo Fisher Scientific, Waltham, MA, USA) using the ATR measurement technique (see Supporting Information). Mass spectra were recorded on a AccuTOF LC-plus 4G Mass Spectrometer (JEOL, Akishima, Japan).

4.1. Preparation of Compounds 1a, 1b and 2–7

4.1.1. 3,4,5-Triphenyltoluene (5)

Compound 4 (3.00 g, 9.12 mmol) was dissolved in toluene (50 mL) and a 2 M Na₂CO₃ solution (15 mL), EtOH (50 mL) and phenylboronic acid (3.34 g, 27.37 mmol) were added. After the addition of a Pd(PPh₃)₄ solution (5 mol%, 0.527 g, 0.456 mmol), the reaction mixture was refluxed for 3 d. The slurry was cooled to room temperature and filtered. The organic phase was separated and the aqueous phase was extracted twice with EtOAc (15 mL). The combined organic phases were washed once with water, dried over MgSO₄, and the solvent was removed under reduced pressure. The resulting oily-yellow residue was stored at room temperature and a small portion of CHCl₃ was added, allowing the crude product to solidify. The resulting solid was filtered off and recrystallized from MeOH. This process yielded 68% of compound 5 (1.98 g, 6.18 mmol); M.p. 118–119 °C. ¹H NMR (500 MHz, CDCl₃): δ = 2.46–2.47 (m, 3H, CH₃), 6.80–6.83 (m, 2H, C_ArH), 6.93–6.98 (m, 3H, C_ArH), 7.06–7.09 (m, 4H, C_ArH), 7.11–7.16 (m, 6H, C_ArH), 7.26–7.27 (m, 2H, C_ArH) ppm. ¹³C-NMR (125 MHz, CDCl₃): δ = 21.2, 125.8, 126.2, 127.3, 127.6, 130.0, 130.5, 131.9, 136.5, 137.0, 139.6, 142.0, 142.1 ppm. IR (ATR): ῡ = 3053 (υ CH_Ar), 3020 (υ CH_Ar), 2915 (υ_as CH₃), 2854 (υ_s CH₃), 1951, 1888, 1807, 1770, 1602, 1575, 1494, 1459, 1442, 1427 (δ CH₃), 1280, 1180, 1153, 1072, 1029, 1006, 921, 910, 871, 842, 788, 763, 750, 698 (δ CH_Ar), 628, 617, 601, 578, 565, 505, 406 cm⁻¹. HRMS-ESI: calcd. for C₂₅H₂₁ [M + H]⁺: 321.1637, found: 321.1622 (Δm = −1.56 mDa).

4.1.2. 3,4,5-Triphenylbenzyl Bromide (6)

Compound 5 (1.00 g, 3.12 mmol) and N-bromosuccinimide (0.28 g, 1.56 mmol) were dissolved in carbon tetrachloride (20 mL) and a spatula tip of AIBN was added. The mixture was refluxed for 20 min, cooled to room temperature, and the solvent was removed in vacuo. The residue was dissolved in chloroform (30 mL), washed with brine and water, and then dried over MgSO₄. The solvent was evaporated and the residue recrystallized from n-hexane. This process yielded 73% of compound 6 (0.90 g, 2.25 mmol); M.p. 164–165 °C. ¹H NMR (500 MHz, CDCl₃): δ = 4.60 (s, 2H, CH₂), 6.79–6.83 (m, 2H, C_ArH), 6.94–7.00 (m, 3H, C_ArH), 7.05–7.09 (m, 4H, C_ArH), 7.13–7.17 (m, 6H, C_ArH), 7.46 (s, 2H, C_ArH) ppm. ¹³C-NMR (125 MHz, CDCl₃): δ = 33.3, 126.2, 126.5, 127.4, 127.7, 129.9, 130.3, 131.6, 136.8, 139.0, 139.4, 141.4, 142.6 ppm. IR (ATR): ῡ = 3108 (υ CH_Ar), 3083 (υ CH_Ar), 3056 (υ CH_Ar), 3035 (υ CH_Ar), 3022 (υ CH_Ar), 2923 (υ_as CH₂), 2852 (υ_s CH₂), 1951, 1880, 1805, 1758, 1600, 1575, 1560, 1492, 1457, 1446, 1434, 1425, 1415 (δ CH₂), 1390, 1334, 1311, 1280, 1268, 1259, 1243, 1211, 1182, 1153, 1137, 1106, 1072, 1031, 1006, 989, 970, 923, 910, 889, 877, 842, 823, 792, 763, 752, 696 (δ CH_Ar), 667, 653, 626, 597, 576, 543, 511, 491, 406 cm⁻¹. HRMS-ESI: calcd. for C₂₅H₁₉BrNa [M + Na]⁺: 423.0545, found: 423.0571 (Δm = 2.58 mDa).

4.1.3. 2-[(3,4,5-Triphenyl)phenyl]acetonitrile (7)

Compound 6 (300 mg, 0.75 mmol), KCN (54 mg, 0.83 mmol), and 18-crown-6 (60 mg, 0.23 mmol) were placed in a round bottom flask and abs. acetonitrile (10 mL) was added. The mixture was refluxed for 3 d and the solvent evaporated afterwards. The crude product was purified via flash chromatography [eluent CHCl₃:hexanes 3:1 (v/v)], and recrystallized from a cyclohexane/dioxane mixture. This process yielded 64% of compound 7 (165 mg, 0.47 mmol); M.p. 152–153 °C. ¹H NMR (500 MHz, CDCl₃): δ = 3.85 (s, 2H, CH₂), 6.79–6.82 (m, 2H, C_ArH), 6.95–7.01 (m, 3H, C_ArH), 7.04–7.08 (m, 4H, C_ArH), 7.14–7.18 (m, 6H, C_ArH), 7.39 (s, 2H, C_ArH) ppm. ¹³C-NMR (125 MHz, CDCl₃): δ = 23.4, 117.8, 126.1, 126.6, 127.3, 127.7, 128.9, 129.0, 129.7, 131.5, 138.7, 139.1, 141.0, 142.9 ppm. IR (ATR): ῡ = 3108 (υ CH_Ar), 3083 (υ CH_Ar), 3054 (υ CH_Ar), 3037 (υ CH_Ar), 2958, 2921 (υ_as CH₂), 2858 (υ_s CH₂), 2250(υ C$\equiv$N), 1959, 1897, 1820, 1805, 1762, 1695, 1600, 1565, 1492, 1463, 1446, 1417 (δ CH₂), 1361, 1328 1313, 1297, 1278, 1253, 1234, 1187, 1182, 1162, 1120, 1082, 1029, 1008, 997, 981, 971, 939, 925, 916, 896, 889, 865, 854, 844, 811, 792, 763, 746, 728, 696 (δ CH_Ar), 676, 630, 617, 607, 595, 568, 524, 514, 493, 455, 416 cm⁻¹. HRMS-ESI: calcd. for C₂₆H₁₉NNa [M + Na]⁺: 368.1410, found: 368.1418 (Δm = 0.86 mDa).

4.1.4. 2-[(3,4,5-Triphenyl)phenyl]acetamide (2)

Compound 7 (300 mg, 0.87 mmol) was refluxed for 6 h in a solution of HBr in acetic acid (33% of HBr, 75 mL). The cooled reaction mixture was poured onto a small amount of water and the resulting white precipitate was extracted with diethyl ether. The combined organic phases were washed with water and then dried over Na₂SO₄. The solvent was removed using a rotary evaporator and the oily yellow-brown crude product was recrystallized from cyclohexane/dioxane. This process yielded 71% of compound 2 (224 mg, 0.61 mmol); M.p. 171–173 °C. ¹H NMR (500 MHz, CDCl₃): δ = 3.68 (s, 2H, CH₂), 5.68 (s, 1H, NH), 6.08 (s, 1H, NH), 6.79–6.83 (m, 2H, C_ArH), 6.93–7.00 (m, 3H, C_ArH), 7.04–7.08 (m, 4H, C_ArH), 7.12–7.16 (m, 6H, C_ArH), 7.35 (s, 2H, C_ArH) ppm. ¹³C-NMR (125 MHz, CDCl₃): δ = 43.0, 126.1, 126.5, 127.4, 127.7, 129.9, 130.6, 131.7, 133.9, 138.4, 139.1, 141.5, 142.7, 173.7 ppm. IR (ATR): ῡ = 3346 (υ NH₂), 3319 (υ NH₂), 3155(υ NH₂), 3058(υ NH₂), 3053 (υ CH_Ar), 3049 (υ CH_Ar), 2964, 2910 (υ_as CH₂), 2856 (υ_s CH₂), 1683 (υ C=O), 1658, 1598, 1573, 1490, 1446, 1390, 1382, 1268, 1253, 1213, 1180, 1157, 1112, 1074, 1027, 1010, 993, 900, 890, 865, 848, 815, 790, 763, 744, 698 (δ CH_Ar), 651, 600, 515, 499, 430 cm⁻¹. HRMS-ESI: calcd. for C₂₆H₂₂NO [M + H]⁺: 364.1696, found: 364.1710 (Δm = 1.37 mDa).

4.1.5. 2-[(3,4,5-Triphenyl)phenyl]acetic Acid (1a)

From compound 2. In a 9:1 (v/v) mixture of dioxane/water (2 mL), compound 2 (100 mg, 0.28 mmol) was dissolved and titanium chloride (5.2 mg, 0.03 mmol) and conc. HCl (28 mg, 0.28 mmol) were added. The reaction was refluxed for 2 h. After cooling, the mixture was poured into water (2 mL) and the aqueous phase was extracted with EtOAc (3 × 3 mL). The combined organic layers were dried over Na₂SO₄ and the solvent was removed in vacuo. The obtained solid was recrystallized from toluene and acetonitrile. This process yielded 85% of compound 1a (87 mg, 0.24 mmol).

From compound 7. Compound 7 (200 mg, 0.58 mmol) and KOH (162 mg, 2.89 mmol) were refluxed for 2 d in methanol (aq) (10 mL). The solvent was removed and the residue was dissolved in warm water (20 mL). Afterwards, conc. sulfuric acid was added dropwise, until no more precipitate was formed. The precipitate was filtered off and dried in vacuo. The crude product was first recrystallized from toluene and then from MeCN. This process yielded 27% of compound 1a (56 mg, 0.15 mmol).

M.p. 198 °C. ¹H NMR (500 MHz, DMSO-d₆): δ = 3.72 (s, 2H, CH₂), 6.80–6.84 (m, 2H, C_ArH), 6.97–7.00 (m, 4H, C_ArH), 7.02–7.04 (m, 4H, C_ArH), 7.13–7.18 (m, 6H, C_ArH), 7.30 (s, 2H, CH_Ar) ppm. ¹³C-NMR (125 MHz, DMSO-d₆): δ = 40.2 126.1, 126.4, 127.3, 127.7, 129.6, 130.5, 131.3, 134.3, 137.1, 139.1, 141.4, 172.8 ppm. IR (ATR): ῡ = 3434 (υ C=O, overtone), 3081 (υ CH_Ar), 3054 (υ CH_Ar), 3023 (υ CH_Ar), 2964, 2912 (υ_as CH₂), 2846 (υ_s CH₂), 2630 (υ OH_Acid), 2536 (υ OH_Acid), 1699 (υ C=O), 1600, 1575, 1492, 1459, 1446, 1417 (δ CH₂), 1403, 1346, 1311, 1305, 1234, 1182, 1157, 1153, 1126, 1074, 1027, 1008, 943, 914, 871, 848, 792, 763, 744, 696 (δ CH_Ar), 661, 628, 607, 599, 553, 518, 501, 439 cm⁻¹. HRMS-ESI: calcd. for C₂₆H₂₀O₂Na [M + Na]⁺: 387.1356, found: 387.1334 (Δm = −2.12 mDa).

4.1.6. Potassium 2-[(3,4,5-Triphenyl)phenyl]acetate (1b)

Compound 1a (50 mg, 0.14 mmol) was suspended in 1 mL MeOH and a 7.5 N KOH solution (4 mL) was added thereto. The mixture was refluxed for 1 h and stirred at room temperature afterwards.

The solid obtained was filtered off and washed with a small portion of water. This process yielded 80% of compound 1b (44 mg, 0.11 mmol); M.p. >360 °C. ¹H NMR (500 MHz, CD₃OD) δ = 3.60 (s, 2H, CH₂), 6.76–6.80 (m, 2H, C_ArH), 6.90–6.97 (m, 3H, C_ArH), 7.03–7.07 (m, 4H, C_ArH), 7.08–7.13 (m, 6H, C_ArH), 7.37 (s, 2H, C_ArH) ppm. ¹³C-NMR (125 MHz, CD₃OD): δ = 46.1, 126.7, 127.0, 128.1, 128.5, 131.0, 131.4, 132.9, 138.0, 138.4, 141.2, 143.0, 143.5, 180.2 ppm. IR (ATR): ῡ = 3592, 3320 (H₂O), 3201, 3083 (υ CH_Ar), 3060 (υ CH_Ar), 3050 (υ CH_Ar), 3035 (υ CH_Ar), 2944, 2923 (υ_as CH₂), 2858 (υ_s CH₂), 1556, 1492, 1444, 1421 (δ CH₂), 1376, 1270, 1180, 1159, 1151, 1072, 1029, 1008, 931, 916, 869, 850, 813, 790, 746, 698 (δ CH_Ar), 667, 597, 547, 518, 512, 431 cm⁻¹. HRMS-ESI: calcd. for C₂₆H₂₀KO₂⁺[M + H]⁺: 403.1095, found: 403.1092 (Δm = −0.25 mDa).