CC BY ND NC 4.0 · SynOpen 2017; 01(01): 0091-0096
DOI: 10.1055/s-0036-1588550
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Copyright with the author

Palladium-Catalyzed α-Arylation of Dimethyl Malonate and Ethyl Cyanoacetate with o-Alkoxybromobenzenes for the Synthesis of Phenylacetic Acid, Esters and Phenylacetonitriles

José F. Cívicosa, Paulo R. R. Costa*a, Jorge L. O. Domingos*b
  • aInstituto de Pesquisas de Produtos Naturais, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, 21941-590, Rio de Janeiro, RJ, Brazil   Email: prrcosta2011@gmail.com
  • bDep. Química Orgânica, Instituto de Química, Centro de Tecnologia e Ciências, Universidade do Estado do Rio de Janeiro, 20550-900, Rio de Janeiro, RJ, Brazil
We thank the Brazilian agencies Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES; BJT-2014), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and Fundação Carlos­ Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ).
Further Information

Publication History

Received: 28 July 2017

Accepted after revision: 01 August 2017

Publication Date:
22 August 2017 (online)

 

Abstract

α-Aryl malonate and α-aryl cyano acetate moieties are found in the structures of many bioactive compounds. They are also key intermediates for the synthesis of many compounds such as isoflavonoids. In this work, we synthesized these compounds, with different patterns of substitution, starting with the palladium-catalyzed reaction of o-alkoxy-bromoarenes with dimethyl malonate or ethyl cyanoacetate. Under the conditions applied, moderate to good yields of arylmalonate mono­esters, phenylacetic esters or acids, and benzylnitrile derivatives were obtained.


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α-Aryl malonates are found as substructures in bioactive compounds such as isoquinoline-1,3-dione, an HIV-1 integrase inhibitor,[1] and in barbiturates such as alphenal.[2] They can also be used as intermediates for the synthesis of 3-hydroxy-2-phenylpropanoic acid derivatives, through the reduction of one carboxylate group, to obtain tropic acid derivatives such as the tropane alkaloid scopolamine, an antiemetic drug.[3] The decarboxylation reaction of α-aryl dicarbonyl compounds leads to α-phenylacetic acids, which are found for example in the structure of ibuprofen (anti-inflammatory activity),[4] in UPF523 (active in the CNS),[5] and in JSTX-3 (a neurotoxin found in spider venom).[6] They have also been used in the total synthesis of isoflavonoids such as cajanol and daidzein.[7] Phenylacetonitriles are used in the synthesis of isoflavonoids,[8] and reduction of the nitrile group gives rise to phenylethylamines.[9] These are found in pharmaceuticals such as the antiarrithimic verapamil and the anticancer drug anastrazole.[10] The structures of these compounds are shown in Figure [1].

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Figure 1 Bioactive compounds with α-arylmalonate, phenylacetic and benzylnitrile moieties

The alkylation of malonates is a useful approach to prepare intermediates in organic synthesis.[11] However, this approach is limited to primary and secondary alkyl halides and halobenzenes substituted with electron-withdrawing groups.[12] Our interest lies in the synthesis of oxygenated α-aryl carbonyl structures, which are used as precursors of isoflavonoid natural products, and these compounds cannot be prepared through the SNAr approach.[12] In this paper, we report the synthesis of α-arylmalonates (1; R1 = R2 = alkyl­) and α-arylcyanoacetates 5 by α-arylation of malonates and cyanoacetates with aryl halides and their transformations into the desired compounds 26, as shown in Figure [2].

Zoom Image
Figure 2 α-Arylmalonates, phenylacetic acid derivatives, and phenyl­acetonitriles synthesized in this work

The α-arylation reaction of carbonyl compounds has been studied since the early eighties, and more extensively and independently studied by Buchwald, Hartwig and Miura­.[13] Since then, various metal catalysts, ligands, and conditions have been developed for this reaction.[14] Our approach was based on the α-arylation of malonates and cyanoacetates catalyzed by palladium. Although these reactions have been well studied, little attention has been given to the use of the more sterically hindered o-alkoxy-bromoarenes as the arylating agents, leading to compounds of type 1 and 5. In addition, very few oxygenation patterns at the aromatic ring have been examined using these α-arylations.

The α-arylation step was optimized using the reaction of o-bromoanisole and dimethyl malonate or ethyl cyanoacetate (Scheme [1]). After 20 h at 70 °C in toluene in the presence of Pd2(dba)3, the corresponding arylmalonate 1a was obtained in 60% yield.[15] Aryl-cyano acetate 5a was prepared, under the same conditions (15 h), in 66% yield (Scheme [1]).[16] Both compounds were purified by flash column chromatography. Other O-protected bromoarenes were used under the same conditions and the α-arylmalonates 1be and α-arylcyanoacetates 5b,c were obtained in yields ranging from 41 to 83% (Scheme [1]). By using this methodology, we were able to prepare derivatives that were O-benzylated in the ortho-position (41–83%), which is a protecting group that can be removed under less drastic conditions than those used to remove methyl groups.[17] This is the first time that compounds 1c, 1d and 5c have been synthesized.

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Scheme 1 α-Arylation reactions. Reagents and conditions: (i) Pd2(dba)3 (2.5% mol), tBu3PHBF4 (10% mol), K3PO4 (3 equiv), toluene, 20 h/70 °C (for 1ae); Na3PO4 (3 equiv), 15 h/70 °C (for 5ac).

The monohydrolysis of arylmalonates has been described under basic or acidic conditions.[18] In our hands, in the presence of KOH in THF–H2O at 0 °C the aryl-monomethyl malonate 2a was obtained in low yield as a mixture with the unreacted arylmalonate and the decarboxylation product. The same outcome was observed when KOH/MeOH at 35 °C was used. However, the desired product 2a was obtained in good yield when KOH was used in a mixture of MeOH/H2O (10:1, v/v), at 36 °C after 2 h (Scheme [2]). Under the same conditions, arylmalonates 1be were hydrolyzed to the corresponding aryl monomethyl malonates 2be in yields ranging from 70 to 89%.

Zoom Image
Scheme 2 Monohydrolysis of arylmalonates. Reagents and conditions: (i) KOH (2 equiv), MeOH/H2O (10:1, v/v), 36 °C, 2 h.

The one-pot hydrolysis followed by decarboxylation was successfully used to obtain, selectively, either arylacetate esters or the arylacetic acids, by changing the reaction conditions. When the temperature was increased to 80 °C, methyl esters of arylacetates 3ae were obtained in moderate to high yields (Scheme [3]). By increasing the amount of base from 2 to 3 equivalents and raising the temperature to 90 °C, under microwave irradiation, arylacetic acids 4ae were produced in high yields (80–100%) (Scheme [3]).

Zoom Image
Scheme 3 Hydrolysis/decarboxylation reactions. Reagents and conditions: For 3ae: (i) KOH (2 equiv), MeOH/H2O (10:1, v/v), 90 °C, 2.5 h; for 4ae: (ii) KOH (3 equiv), MeOH/H2O (10:1, v/v), 90 °C, 150 W, 20 min.

The hydrolysis/decarboxylation of aryl-cyanoacetates 5 was performed under the same conditions and benzyl­nitriles 6ab were obtained in high yields (Scheme [4]).

Zoom Image
Scheme 4 Hydrolysis/decarboxylation reactions. Reagents and conditions: (i) KOH (3 equiv), MeOH/H2O (10:1, v/v), 90 °C, 150 W, 20 min.

In conclusion, selected products from palladium-catalyzed­ α-arylation reactions of dimethyl malonates and ethyl cyanoacetates with bromoarenes were obtained in moderate to good yields. Some of these compounds, with the benzyl protecting group on the phenol functionality (1c, 1d, 5c),[19] [20] were obtained for the first time in this work.

The arylmalonates could be transformed directly into the phenylacetic acids or the corresponding methyl esters (3ae, 4ae). Arylacetonitriles 6ab could also be prepared from arylcyanoacetates 5ac through one-pot hydrolysis followed by decarboxylation.

1H NMR (400 MHz) and 13C NMR (75 MHz) spectra were obtained with a Varian Gemini-200 with CDCl3 as solvent and TMS as internal standard unless otherwise stated. High-resolution mass spectra were obtained at 70 eV by electron impact with direct insertion on a Micromass MM12F. Analytical TLC was performed on Merck aluminum sheets with silica gel 60 F254. For flash chromatography, Merck silica gel 60 (0.040–0.063 mm) was used. Melting points were determined with a Fisatom 430 apparatus and are uncorrected.


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Arylation of Dimethyl Malonate with Aryl Bromides; General Procedure

Dimethyl malonate (1 mmol), aryl bromide (1.1 mmol), [HP(tBu)3]BF4 (0.10 mmol), Pd2(dba)3 (0.025 mmol), and K3PO4 (3.0 mmol) were placed in a 25 mL round-bottomed flask with a magnetic stirrer. The flask was closed with a septum, the contents were placed under an argon atmosphere and anhydrous toluene (5.0 mL) was added. The heterogeneous mixture was stirred at 70 °C and the reaction was monitored by TLC. Upon complete consumption of the aryl bromide, the crude reaction mixture was filtered through a plug of Celite®, extracted with EtOAc (3 × 10 mL), washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (1:9, EtOAc/hexanes).


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Dimethyl 2-(2-Methoxyphenyl)malonate (1a)[21]

Yield: 0.143 g (60%); yellow oil; Rf 0.16 (1:9, EtOAc/hexanes).

1H NMR (CDCl3, 400 MHz): δ = 7.36–7.28 (m, 2 H), 6.97 (td, J = 7.5, 1.0 Hz, 1 H), 6.90 (d, J = 8.1 Hz, 1 H), 5.16 (s, 1 H), 3.82 (s, 3 H), 3.75 (s, 6 H).

13C NMR (CDCl3, 100 MHz): δ = 169.0, 156.8, 129.5, 129.4, 121.5, 120.7, 110.7, 55.6, 52.7, 50.7.


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Dimethyl 2-(2,4-Dimethoxyphenyl)malonate (1b)

Yield: 0.209 g (78%); brown solid; mp 60–62 °C; Rf 0.26 (1:9 EtOAc­/hexanes).

1H NMR (CDCl3, 400 MHz): δ = 7.25 (d, J = 8.5 Hz, 1 H), 6.50 (dd, J = 8.5, 2.4 Hz, 1 H), 6.46 (d, J = 2.3 Hz, 1 H), 5.07 (s, 1 H), 3.79 (s, 6 H), 3.74 (s, 6 H).

13C NMR (CDCl3, 100 MHz): δ = 169.3, 168.9, 160.8, 157.8, 130.1, 113.9, 104.5, 98.6, 55.6, 55.3, 52.7, 50.1, 48.9.

HRMS: m/z calcd for C13H16O6: 268.0947; found: 268.0946.


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Dimethyl 2-(2-(Benzyloxy)-4-methoxyphenyl)malonate (1c)

Yield: 0.285 g (83%); yellow solid; mp 61–63 °C; Rf 0.21 (1:9 EtOAc­/hexanes).

1H NMR (CDCl3, 400 MHz): δ = 7.40–7.32 (m, 4 H), 7.30 (dd, J = 6.0, 2.7 Hz, 1 H), 7.25 (d, J = 8.1 Hz, 1 H), 6.51 (s, 1 H), 6.49 (d, J = 2.4 Hz, 1 H), 5.12 (s, 1 H), 5.02 (s, 2 H), 3.73 (s, 3 H), 3.68 (s, 6 H).

13C NMR (CDCl3, 100 MHz): δ = 169.3, 160.8, 157.0, 136.6, 130.2, 128.64, 128.0, 127.3, 114.5, 105.0, 99.9, 70.4, 55.5, 52.8, 50.7.

HRMS: m/z calcd for C19H20O6: 344.1260; found: 344.1259.


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Dimethyl 2-(2,4-Bis(benzyloxy)phenyl)malonate (1d)

Yield: 0.223 g (53%); yellow solid; mp 103–105 °C; Rf 0.16 (1:9 EtOAc­/hexanes).

1H NMR (CDCl3, 400 MHz): δ = 7.42–7.29 (m, 8 H), 7.24 (q, J = 4.5 Hz, 2 H), 7.14 (d, J = 8.1 Hz, 1 H), 6.60 (d, J = 2.2 Hz, 1 H), 6.58 (dd, J = 8.4, 2.3 Hz, 1 H), 5.12 (s, 1 H), 5.03 (s, 2 H), 5.01 (s, 2 H), 3.71 (s, 6 H).

13C NMR (CDCl3, 100 MHz): δ = 169.4, 160.1, 157.1, 139.5, 136.8, 136.6, 128.8, 128.7, 128.2, 128.1, 127.8, 127.7, 127.3, 123.0, 106.0, 100.8, 70.4, 70.3, 52.83, 52.83, 50.8.

HRMS: m/z calcd for C25H24O6: 420.1573; found: 420.1572.


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Dimethyl 2-(6-(Benzyloxy)benzo[d][1,3]dioxol-5-yl)malonate (1e)

Yield: 0.254 g (71%); brown solid; mp 87–89 °C; Rf 0.10 (1:9 EtOAc­/hexanes).

1H NMR (CDCl3, 400 MHz): δ = 7.39–7.29 (m, 5 H), 6.88 (s, 1 H), 6.57 (s, 1 H), 5.90 (s, 2 H), 5.16 (s, 1 H), 5.00 (s, 2 H), 3.71 (s, 6 H).

13C NMR (CDCl3, 125 MHz): δ = 169.0, 151.3, 148.1, 141.7, 136.6, 128.5, 128.1, 127.4, 127.2, 114.1, 109.2, 109.2, 101.4, 96.4, 96.3, 71.7, 52.8, 52.7, 50.7, 50.5.

HRMS: m/z calcd for C19H18O7: 358.1053; found: 358.1052.


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Arylation of Ethyl Cyanoacetate with Aryl Bromides; General Procedure

Ethyl cyanoacetate (1.1 mmol), aryl bromide (1.0 mmol), [HP(tBu)3]BF4 (0.10 mmol), Pd2(dba)3 (0.025 mmol, and Na3PO4 (3.0 mmol) were placed in a 25 mL round-bottom flask. The flask was closed with a septum, the contents were placed under an argon atmosphere and anhydrous toluene (5.0 mL) was added. The heterogeneous reaction mixture was stirred at 70 °C and monitored by TLC. Upon complete consumption of the aryl bromide, the crude reaction mixture was filtered through a plug of Celite®, extracted with EtOAc (3 × 10 mL), washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (1:9 EtOAc/hexanes).


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Ethyl 2-Cyano-2-(2-methoxyphenyl)acetate (5a)[22]

Yield: 0.144 g (66%); yellow oil; Rf 0.12 (1:9 EtOAc/hexanes).

1H NMR (CDCl3, 400 MHz): δ = 7.36 (dd, J = 12.2, 4.5 Hz, 2 H), 6.99 (t, J = 7.5 Hz, 1 H), 6.93 (d, J = 8.2 Hz, 1 H), 5.03 (s, 1 H), 4.24 (dd, J = 7.2, 4.2 Hz, 2 H), 3.84 (s, 3 H), 1.27 (t, J = 7.1 Hz, 2 H).

13C NMR (CDCl3, 125 MHz): δ = 165.1, 156.4, 130.6, 129.3, 120.9, 119.0, 115.8, 111.0, 62.8, 55.6, 38.1, 24.5, 13.8.


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Ethyl 2-Cyano-2-(2,4-dimethoxyphenyl)acetate (5b)[23]

Yield: 0.137 g (55%); red brown oil; Rf 0.13 (1:9 EtOAc/hexanes).

1H NMR (CDCl3, 400 MHz): δ = 7.39 (ddd, J = 12.3, 6.6, 1.4 Hz, 2 H), 7.01 (td, J = 7.6, 0.9 Hz, 1 H), 6.94 (d, J = 8.2 Hz, 1 H), 5.03 (s, 1 H), 4.27 (qd, J = 7.1, 1.4 Hz, 2 H), 3.87 (s, 3 H), 1.32–1.27 (m, 3 H).

13C NMR (CDCl3, 125 MHz): δ = 165.5, 161.7, 157.5, 130.0, 116.2, 111.5, 104.9, 98.9, 62.9, 55.7, 55.5, 37.6, 14.0.


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Ethyl 2-(2-(Benzyloxy)-4-methoxyphenyl)-2-cyanoacetate (5c)

Yield: 0.139 g (41%); yellow oil; Rf 0.14 (1:9 EtOAc/hexanes).

1H NMR (CDCl3, 500 MHz): δ = 7.44–7.37 (m, 4 H), 7.33 (dd, J = 13.5, 7.8 Hz, 2 H), 6.54 (d, J = 6.9 Hz, 2 H), 5.08 (q, J = 11.5 Hz, 2 H), 4.95 (s, 1 H), 4.15 (q, J = 7.0 Hz, 2 H), 3.80 (s, 3 H), 1.19 (t, J = 7.1 Hz, 3 H).

13C NMR (CDCl3, 125 MHz): δ = 165.5, 161.7, 156.6, 136.1, 130.3, 128.8, 128.8, 128.7, 128.7, 128.2, 127.4, 116.2, 111.8, 105.2, 100.1, 70.5, 62.9, 55.5, 38.0, 13.9.

HRMS: m/z calcd for C19H19NO4: 325.1314; found: 325.1314.


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Selective Monohydrolysis of Dimethyl Arylmalonates; General Procedure

Dimethyl arylmalonate (1.0 mmol) and KOH (2.0 mmol), followed by MeOH (1.0 mL) and H2O (0.1 mL) were placed in a 25 mL round-bottom­ flask with a magnetic stirrer. The mixture was stirred at 36 °C for 2 h, then the reaction was quenched by the addition of water (5 mL). Unreacted ester was removed by EtOAc extraction (2 × 5 mL) and the carboxylic acid was obtained by acidification of the aqueous phase to pH 2 with 10% HCl, extracted with EtOAc (3 × 5 mL), washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated on a rotary evaporator.


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3-Methoxy-2-(2-methoxyphenyl)-3-oxopropanoic Acid (2a)

Yield: 0.134 g (60%); brown oil.

1H NMR (CDCl3, 500 MHz): δ = 7.22 (d, J = 7.5 Hz, 1 H), 7.20–7.15 (m, 1 H), 6.81 (t, J = 7.4 Hz, 1 H), 6.77 (d, J = 8.2 Hz, 1 H), 6.40 (s, 1 H), 4.90 (s, 1 H), 3.67 (s, 3 H), 3.57 (s, 3 H).

13C NMR (CDCl3, 100 MHz): δ = 173.1, 169.6, 156.8, 129.8, 129.8, 121.4, 120.8, 110.9, 55.7, 53.0, 50.9.

HRMS: m/z calcd for C11H12O5: 224.0685; found: 224.0684.


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2-(2,4-Dimethoxyphenyl)-3-methoxy-3-oxopropanoic Acid (2b)[24]

Yield: 0.221 g (87%); pale-brown solid; mp 108–110 °C.

1H NMR (CDCl3, 500 MHz): δ = 7.26 (d, J = 3.4 Hz, 1 H), 6.51 (dd, J = 8.5, 2.4 Hz, 1 H), 6.47 (d, J = 2.3 Hz, 1 H), 4.92 (s, 1 H), 3.81 (s, 3 H), 3.80 (s, 3 H), 3.76 (s, 3 H).

13C NMR (CDCl3, 100 MHz): δ = 173.8, 169.7, 160.9, 157.8, 130.4, 113.6, 104.7, 98.7, 55.7, 55.4, 52.9, 50.3.


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2-(2-(Benzyloxy)-4-methoxyphenyl)-3-methoxy-3-oxopropanoic Acid (2c)

Yield: 0.274 g (83%); pale-brown solid; mp 165–167 °C.

1H NMR (CDCl3, 500 MHz): δ = 8.98 (s, 1 H), 7.35 (q, J = 7.9 Hz, 4 H), 7.31–7.23 (m, 2 H), 6.62–6.38 (m, 2 H), 5.04 (s, 1 H), 5.03 (s, 2 H), 3.76 (s, 3 H), 3.69 (s, 3 H).

13C NMR (CDCl3, 100 MHz): δ = 171.5, 171.0, 161.1, 156.9, 136.3, 131.0, 128.7, 128.2, 127.4, 114.4, 105.2, 100.2, 70.6, 55.5, 53.2, 50.7.

HRMS: m/z calcd for C18H18O6: 330.1103; found: 330.1103.


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2-(2,4-Bis(benzyloxy)phenyl)-3-methoxy-3-oxopropanoic Acid (2d)

Yield: 0.284 g (70%); pale-brown solid; mp 90–92 °C.

1H NMR (CDCl3, 500 MHz): δ = 7.50–7.24 (m, 11 H), 6.69–6.54 (m, 2 H), 5.08–4.96 (m, 4 H), 4.87 (s, 1 H), 3.71 (s, 3 H).

13C NMR (CDCl3, 125 MHz): δ = 171.5, 170.3, 160.5, 156.8, 136.7, 136.3, 128.8, 128.7, 128.3, 128.2, 128.2, 127.8, 127.7, 127.5, 127.4, 114.8, 106.1, 100.9, 70.6, 70.4, 53.2, 50.6.

HRMS: m/z calcd for C24H22O6: 406.1416; found: 406.1416.


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2-(6-(Benzyloxy)benzo[d][1,3]dioxol-5-yl)-3-methoxy-3-oxo­propanoic Acid (2e)

Yield: 0.306 g (89%); yellow oil.

1H NMR (CDCl3, 400 MHz): δ = 8.51 (s, 1 H), 7.43–7.23 (m, 5 H), 6.88 (s, 1 H), 6.57 (s, 1 H), 5.91 (s, 2 H), 5.09 (s, 1 H), 5.00 (s, 2 H), 3.72 (s, 3 H).

13C NMR (CDCl3, 125 MHz): δ = 172.5, 170.1, 151.4, 148.5, 141.8, 136.5, 128.8, 128.74, 128.68, 127.5, 127.4, 113.8, 109.8, 101.7, 96.4, 71.8, 53.1, 50.8.

HRMS: m/z calcd for C18H16O7: 344.0896; found: 344.0896.


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Synthesis of α-Arylacetates; General Procedure

Dimethyl arylmalonate (1.0 mmol) and KOH (2.0 mmol), followed by MeOH (1.0 mL) and H2O (0.1 mL) were placed in a 25 mL round-bottom flask with a magnetic stirrer. The mixture was stirred at 80 °C for 2.5 h, then the reaction was quenched by the addition of water (5 mL). The α-arylacetate was removed by EtOAc extraction (3 × 5 mL) and the carboxylic acid was obtained by acidification of the aqueous phase to pH 2 with 10% HCl, extracted with EtOAc (3 × 5 mL), washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated on a rotary evaporator.


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Methyl 2-(2-Methoxyphenyl)acetate (3a)[25]

Yield: 0.135 g (75%); yellow oil.

1H NMR (CDCl3, 400 MHz): δ = 7.27–7.22 (m, 1 H), 7.16 (d, J = 7.4 Hz, 1 H), 6.90 (t, J = 7.2 Hz, 1 H), 6.86 (d, J = 8.2 Hz, 1 H), 3.80 (s, 3 H), 3.67 (s, 3 H), 3.62 (s, 2 H).

13C NMR (CDCl3, 100 MHz): δ = 172.41, 157.55, 130.92, 128.65, 123.03, 120.56, 110.52, 55.50, 51.98, 35.83.


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Methyl 2-(2,4-Dimethoxyphenyl)acetate (3b)[26].

Yield: 0.162 g (77%); yellow oil.

1H NMR (CDCl3, 400 MHz): δ = 7.08 (d, J = 8.6 Hz, 1 H), 6.48–6.41 (m, 2 H), 3.80 (s, 3 H), 3.79 (s, 3 H), 3.68 (s, 3 H), 3.56 (s, 2 H).

13C NMR (CDCl3, 125 MHz): δ = 172.7, 160.3, 158.5, 131.2, 115.5, 104.1, 98.6, 55.5, 55.4, 51.9, 35.1.


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Methyl 2-(2-(Benzyloxy)-4-methoxyphenyl)acetate (3c)[27]

Yield: 0.217 g (76%); brown oil.

1H NMR (CDCl3, 400 MHz): δ = 7.45–7.28 (m, 5 H), 7.11 (d, J = 8.2 Hz, 1 H), 6.52 (d, J = 2.2 Hz, 1 H), 6.47 (dd, J = 8.2, 2.3 Hz, 1 H), 5.05 (s, 2 H), 3.78 (s, 3 H), 3.63 (s, 3 H), 3.61 (s, 2 H).

13C NMR (CDCl3, 100 MHz): δ = 172.75, 160.22, 157.54, 137.00, 131.36, 128.61, 127.93, 127.19, 115.92, 104.54, 99.91, 70.04, 55.50, 51.95, 35.55.


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Methyl 2-(2,4-Bis(benzyloxy)phenyl)acetate (3d)[28]

Yield: 0192 g (53%); yellow solid; mp 78–80 °C (lit. 74.5–75 °C).

1H NMR (CDCl3, 400 MHz): δ = 7.44–7.28 (m, 10 H), 7.10 (d, J = 8.3 Hz, 1 H), 6.60 (d, J = 2.2 Hz, 1 H), 6.54 (dd, J = 8.2, 2.3 Hz, 1 H), 5.02 (d, J = 4.0 Hz, 4 H), 3.62 (s, 3 H), 3.61 (s, 2 H).

13C NMR (CDCl3, 100 MHz): δ = 172.7, 159.4, 157.5, 136.9, 136.9, 131.3, 128.7, 128.5, 128.1, 127.9, 127.6, 127.1, 116.1, 105.5, 100.6, 70.2, 69.9, 51.9, 35.5.


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Methyl 2-(6-(Benzyloxy)benzo[d][1,3]dioxol-5-yl)acetate (3e)

Yield: 0.210 g (70%); white solid; mp 105–107 °C.

1H NMR (CDCl3, 500 MHz): δ = 7.47–7.23 (m, 5 H), 6.70 (s, 1 H), 6.56 (s, 1 H), 5.89 (s, 2 H), 4.99 (s, 2 H), 3.63 (s, 3 H), 3.58 (s, 2 H).

13C NMR (CDCl3, 100 MHz): δ = 172.5, 151.6, 147.4, 141.3, 137.0, 128.6, 128.0, 127.2, 115.6, 110.7, 101.3, 96.3, 71.3, 52.0, 35.8.

HRMS: m/z calcd for C17H16O5: 300.0998; found: 300.0997.


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Synthesis of α-Arylacetic Acids; General Procedure

A 10-mL MW vessel was charged with dimethyl arylmalonate (0.20 mmol) and KOH (0.60 mmol), followed by MeOH (2.0 mL) and H2O (0.2 mL). The vessel was sealed with a pressure lock, and the mixture was heated under microwave irradiation (150 W) at 90 °C for 20 min in a CEM Discover MW reactor. After cooling to r.t., the reaction mixture was extracted with EtOAc (3 × 10 mL), and the α-arylacetic acid was obtained by acidification of the aqueous phase to pH 2 with 10% HCl, extracted with EtOAc (3 × 5 mL), washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated on a rotary evaporator.


#

2-(2-Methoxyphenyl)acetic Acid (4a)[29]

Yield: 0.026 g (80%); pale-brown solid; mp 115–117 °C (lit. 119–121 °C).

1H NMR (CDCl3, 500 MHz): δ = 7.29–7.24 (m, 1 H), 7.18 (d, J = 7.3 Hz, 1 H), 6.92 (t, J = 7.4 Hz, 1 H), 6.88 (d, J = 8.2 Hz, 1 H), 3.82 (s, 3 H), 3.66 (s, 2 H).

13C NMR (CDCl3, 100 MHz): δ = 178.2, 157.6, 131.1, 129.0, 122.4, 120.7, 110.6, 55.6, 35.9.


#

2-(2,4-Dimethoxyphenyl)acetic Acid (4b)[30]

Yield: 0.034 g (87%); white solid; mp 90–92 °C (lit. 99–102 °C).

1H NMR (CDCl3, 400 MHz): δ = 7.08 (d, J = 7.8 Hz, 1 H), 6.51–6.40 (m, 2 H), 3.80 (s, 6 H), 3.59 (s, 2 H).

13C NMR (CDCl3, 100 MHz): δ = 177.9, 160.5, 158.5, 131.4, 114.9, 104.3, 98.8, 55.6, 55.5, 35.2.


#

2-(2-(Benzyloxy)-4-methoxyphenyl)acetic Acid (4c)[31]

Yield: 0.046 g (84%); pale-yellow solid; mp 115–117 °C.

1H NMR (CDCl3, 500 MHz): δ = 7.41–7.28 (m, 5 H), 7.11 (d, J = 8.3 Hz, 1 H), 6.52 (d, J = 2.0 Hz, 1 H), 6.48 (dd, J = 8.2, 2.2 Hz, 1 H), 5.05 (s, 2 H), 3.78 (s, 3 H), 3.64 (s, 2 H).

13C NMR (CDCl3, 125 MHz): δ = 177.7, 160.3, 157.5, 136.9, 131.5, 128.7, 128.6, 127.9, 127.1, 127.1, 115.7, 104.6, 99.9, 70.1, 55.5, 35.7.


#

2-(2,4-Bis(benzyloxy)phenyl)acetic Acid (4d)[32]

Yield: 0.070 g (100%); pale-brown solid; mp 134–136 °C (lit. 137–137.5 °C).

1H NMR (CDCl3, 400 MHz): δ = 7.28–7.04 (m, 1 H), 6.92 (d, J = 7.2 Hz, 1 H), 6.39 (s, 1 H), 6.28 (d, J = 7.4 Hz, 1 H), 4.77 (s, 1 H), 4.71 (s, 1 H), 3.38 (s, 1 H).

13C NMR (CDCl3, 100 MHz): δ = 177.4, 158.6, 157.2, 137.1, 131.4, 128.6, 128.5, 127.9, 127.8, 127.7, 127.2, 118.9, 105.7, 101.2, 70.1, 69.9, 29.8.


#

2-(6-(Benzyloxy)benzo[d][1,3]dioxol-5-yl)acetic acid (4e)[33]

Yield: 0.049 g (86%); brown solid; mp 119–122 °C.

1H NMR (400 MHz, acetone-d 6): δ = 7.42 (d, J = 7.4 Hz, 2 H), 7.34 (t, J = 7.4 Hz, 2 H), 7.29 (d, J = 7.3 Hz, 1 H), 6.71 (s, 1 H), 6.66 (s, 1 H), 5.86 (s, 2 H), 5.00 (s, 2 H), 3.54 (s, 2 H).

13C NMR (CDCl3, 125 MHz): δ = 172.9, 152.6, 148.0, 142.0, 138.5, 129.5, 128.9, 128.8, 128.2, 127.9, 117.2, 111.5, 111.4, 102.0, 97.1, 71.7, 35.7.


#

Synthesis of α-Arylacetonitriles; General Procedure

A 10-mL MW vessel was charged with ethyl arylcyanoacetate (0.20 mmol) and KOH (0.60 mmol), followed by MeOH (2.0 mL) and H2O (0.2 mL). The vessel was sealed with a pressure lock, and the mixture was heated under microwave irradiation (150 W) at 90 °C for 20 min in a CEM Discover MW reactor. After cooling to r.t., the reaction mixture was extracted with EtOAc (3 × 10 mL), and the α-arylacetonitrile was obtained by acidification of the aqueous phase to pH 2 with 10% HCl, extracted with EtOAc (3 ×  5 mL), washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated on a rotary evaporator.


#

2-(2-Methoxyphenyl)acetonitrile (6a)[34]

Yield: 0.029 g (100%); yellow oil.

1H NMR (CDCl3, 400 MHz): δ = 7.30 (dd, J = 15.9, 7.9 Hz, 2 H), 6.94 (t, J = 7.4 Hz, 1 H), 6.86 (d, J = 8.2 Hz, 1 H), 3.82 (s, 3 H), 3.64 (s, 2 H).

13C NMR (CDCl3, 100 MHz): δ = 156.6, 129.4, 129.1, 120.6, 118.5, 118.0, 110.4, 55.3, 18.5.


#

2-(2,4-Dimethoxyphenyl)acetonitrile (6b)[35]

Yield: 0.032 g (90%); white solid; mp 70–72 °C (lit. 76 °C).

1H NMR (CDCl3, 400 MHz): δ = 7.23 (d, J = 8.0 Hz, 1 H), 6.48 (d, J = 8.4 Hz, 2 H), 3.84 (s, 2 H), 3.81 (s, 2 H), 3.61 (s, 2 H).

13C NMR (CDCl3, 125 MHz): δ = 161.0, 157.8, 129.7, 118.5, 110.9, 104.3, 98.7, 55.6, 55.5, 18.2.


#
#

Supporting Information

  • References

  • 1 Suchaud V. Bailly F. Lion C. Calmels C. Andréola ML. Christ F. Debyser Z. Cotelle P. J. Med. Chem. 2014; 57: 4640
  • 2 Martin JR. Godel T. Hunkeler W. Jenck F. Moreau J.-L. Sleight AJ. Widmer U. Psychopharmacological Agents . In Kirk-Othmer Encyclopedia of Chemical Technology . 2000
  • 3 Nocquet P.-A. Opatz T. Eur. J. Org. Chem. 2016; 1156
  • 4 Bogdan AR. Poe SL. Kubis DC. Broadwater SJ. McQuade DT. Angew. Chem. Int. Ed. 2009; 48: 8547
  • 5 Costantino G. Pellicciari R. J. Med. Chem. 1996; 39: 3998
  • 6 Barslund AF. Poulsen MH. Bach TB. Lucas S. Kristensen AS. Strømgaard K. J. Nat. Prod. 2011; 74: 483
    • 7a Goel A. Kumar A. Hemberger Y. Raghuvanshi A. Jeet R. Tiwari G. Knauer M. Kureel J. Singh AK. Gautam A. Trivedi R. Singh D. Bringmann G. Org. Biomol. Chem. 2012; 10: 9583
    • 7b Basha GM. Yadav SK. Srinuvasarao R. Prasanthi S. Ramu T. Mangarao N. Siddaiah V. Can. J. Chem. 2013; 91: 763
    • 8a Vasquez-Martinez Y. Ohri RV. Kenyon V. Holman TR. Sepúlveda-Boza S. Bioorg. Med. Chem. 2007; 15: 7408
    • 8b Liu J. Yang Z. Luo S. Hao Y. Ren J. Su Y. Wang W. Li R. Synth. Commun. 2014; 44: 3296
  • 9 Delorme D. Gregor V. Roberts E. Sun E. WO 9967203, 1999 ; Chem. Abstr. 1999, 132, 49802
  • 10 Fleming FF. Yao L. Ravikumar PC. Funk L. Shook BC. J. Med. Chem. 2010; 53: 7902
    • 11a Pearson RG. J. Am. Chem. Soc. 1949; 71: 2212
    • 11b Hoogenboom BE. Ihrig PJ. Langsjoen AN. Linn CJ. Mulder SD. J. Chem. Educ. 1991; 68: 689
    • 12a Yoshida M. Maeyama Y. Shishido K. Tetrahedron 2012; 68: 9962
    • 12b Deng P. Lei Y. Zheng X. Li S. Wu J. Zhu F. Ong BS. Zhang Q. Dyes Pigm. 2016; 125: 407
    • 12c Yoshikawa M. Kamisaki H. Kunitomo J. Oki H. Kokubo H. Suzuki A. Ikemoto T. Nakashima K. Kamiguchi N. Harada A. Kimura H. Taniguchi T. Bioorg. Med. Chem. 2015; 23: 7138
    • 13a Uno M. Seto K. Takahashi S. J. Chem. Soc., Chem. Commun. 1984; 932
    • 13b Uno M. Seto K. Ueda W. Masuda M. Takahashi S. Synthesis 1985; 506
    • 13c Sakamoto T. Kato E. Kondo Y. Yamanaka H. Chem. Pharm. Bull. 1988; 36: 1664
    • 13d Palucki M. Buchwald SL. J. Am. Chem. Soc. 1997; 119: 11108
    • 13e Hartwig JF. Hamann BC. J. Am. Chem. Soc. 1997; 119: 12382
    • 13f Satoh T. Kawamura Y. Miura M. Nomura M. Angew. Chem. Int. Ed. Engl. 1997; 36: 1740
    • 14a Johansson CC. C. Colacot TJ. Angew. Chem. Int. Ed. 2010; 49: 676
    • 14b Bellina F. Rossi R. Chem. Rev. 2010; 110: 1082
  • 15 Beare NA. Hartwig JF. J. Org. Chem. 2002; 67: 541
  • 16 Stauffer SR. Beare NA. Stambuli JP. Hartwig JF. J. Am. Chem. Soc. 2001; 123: 4641
  • 17 Fernandes TA. Domingos JL. O. Rocha LI. A. Medeiros S. Nájera C. Costa PR. R. Eur. J. Org. Chem. 2014; 1314
    • 18a Malki F. Touati A. Rahal S. Moulay S. Asian J. Chem. 2011; 23: 961
    • 18b Niwayama S. Cho H. Lin C. Tetrahedron Lett. 2008; 49: 4434
    • 18c Niwayama S. J. Org. Chem. 2000; 65: 5834
  • 19 Luo M. Liu X. Zu Y. Fu Y. Zhang S. Yao L. Efferth T. Chem.-Biol. Interact. 2010; 188: 151
  • 20 Skouta R. Li CJ. Tetrahedron Lett. 2007; 48: 8343
  • 21 Baciocchi E. Dell’Aira D. Ruzziconi R. Tetrahedron Lett. 1986; 27: 2763
  • 22 Gandi VR. Lu Y. Chem. Commun. 2015; 16188
  • 23 Daikin Kogyo Co. Ltd. Jpn. Kokai Tokkyo Koho JP 59051251 A 19840324, 1984 ; Chem Abstr. 1984, 101, 72461
  • 24 Kamijo T. Tsubaki A. Yamaguchi T. Hirata K. Jpn. Kokai Tokkyo Koho JP 03024047 A 19910201, 1991 ; Chem Abstr. 1991, 115, 49430
  • 25 Jaita S. Phakhodee W. Pattarawarapan M. Synlett 2015; 26: 2006
  • 26 Al-Maharik N. Botting NP. Tetrahedron 2004; 60: 1637
  • 27 van Aardt TG. van Rensburg H. Ferreira D. Tetrahedron 2001; 57: 7113
  • 28 Chiba T. Akizawa T. Matsukawa M. Nishi M. Kawai N. Yoshioka M. Chem. Pharm. Bull. 1996; 44: 972
  • 29 Morton AA. Brachman AE. J. Am. Chem. Soc. 1954; 76: 2973
  • 30 Bernier D. Brückner R. Synthesis 2007; 2249
  • 31 Gray TI. Pelter A. Ward RS. Tetrahedron 1979; 35: 2539
  • 32 Shih TL. Ruiz-Sanchez J. Mrozik H. Tetrahedron Lett. 1987; 28: 6015
  • 33 Pinard E. Gaudry M. Hénot F. Thellend A. Tetrahedron Lett. 1998; 39: 2739
  • 34 Tseng K.-NT. Rizzi AM. Szymczak NK. J. Am. Chem. Soc. 2013; 135: 16352
  • 35 Neill KG. J. Chem. Soc. 1953; 3454

  • References

  • 1 Suchaud V. Bailly F. Lion C. Calmels C. Andréola ML. Christ F. Debyser Z. Cotelle P. J. Med. Chem. 2014; 57: 4640
  • 2 Martin JR. Godel T. Hunkeler W. Jenck F. Moreau J.-L. Sleight AJ. Widmer U. Psychopharmacological Agents . In Kirk-Othmer Encyclopedia of Chemical Technology . 2000
  • 3 Nocquet P.-A. Opatz T. Eur. J. Org. Chem. 2016; 1156
  • 4 Bogdan AR. Poe SL. Kubis DC. Broadwater SJ. McQuade DT. Angew. Chem. Int. Ed. 2009; 48: 8547
  • 5 Costantino G. Pellicciari R. J. Med. Chem. 1996; 39: 3998
  • 6 Barslund AF. Poulsen MH. Bach TB. Lucas S. Kristensen AS. Strømgaard K. J. Nat. Prod. 2011; 74: 483
    • 7a Goel A. Kumar A. Hemberger Y. Raghuvanshi A. Jeet R. Tiwari G. Knauer M. Kureel J. Singh AK. Gautam A. Trivedi R. Singh D. Bringmann G. Org. Biomol. Chem. 2012; 10: 9583
    • 7b Basha GM. Yadav SK. Srinuvasarao R. Prasanthi S. Ramu T. Mangarao N. Siddaiah V. Can. J. Chem. 2013; 91: 763
    • 8a Vasquez-Martinez Y. Ohri RV. Kenyon V. Holman TR. Sepúlveda-Boza S. Bioorg. Med. Chem. 2007; 15: 7408
    • 8b Liu J. Yang Z. Luo S. Hao Y. Ren J. Su Y. Wang W. Li R. Synth. Commun. 2014; 44: 3296
  • 9 Delorme D. Gregor V. Roberts E. Sun E. WO 9967203, 1999 ; Chem. Abstr. 1999, 132, 49802
  • 10 Fleming FF. Yao L. Ravikumar PC. Funk L. Shook BC. J. Med. Chem. 2010; 53: 7902
    • 11a Pearson RG. J. Am. Chem. Soc. 1949; 71: 2212
    • 11b Hoogenboom BE. Ihrig PJ. Langsjoen AN. Linn CJ. Mulder SD. J. Chem. Educ. 1991; 68: 689
    • 12a Yoshida M. Maeyama Y. Shishido K. Tetrahedron 2012; 68: 9962
    • 12b Deng P. Lei Y. Zheng X. Li S. Wu J. Zhu F. Ong BS. Zhang Q. Dyes Pigm. 2016; 125: 407
    • 12c Yoshikawa M. Kamisaki H. Kunitomo J. Oki H. Kokubo H. Suzuki A. Ikemoto T. Nakashima K. Kamiguchi N. Harada A. Kimura H. Taniguchi T. Bioorg. Med. Chem. 2015; 23: 7138
    • 13a Uno M. Seto K. Takahashi S. J. Chem. Soc., Chem. Commun. 1984; 932
    • 13b Uno M. Seto K. Ueda W. Masuda M. Takahashi S. Synthesis 1985; 506
    • 13c Sakamoto T. Kato E. Kondo Y. Yamanaka H. Chem. Pharm. Bull. 1988; 36: 1664
    • 13d Palucki M. Buchwald SL. J. Am. Chem. Soc. 1997; 119: 11108
    • 13e Hartwig JF. Hamann BC. J. Am. Chem. Soc. 1997; 119: 12382
    • 13f Satoh T. Kawamura Y. Miura M. Nomura M. Angew. Chem. Int. Ed. Engl. 1997; 36: 1740
    • 14a Johansson CC. C. Colacot TJ. Angew. Chem. Int. Ed. 2010; 49: 676
    • 14b Bellina F. Rossi R. Chem. Rev. 2010; 110: 1082
  • 15 Beare NA. Hartwig JF. J. Org. Chem. 2002; 67: 541
  • 16 Stauffer SR. Beare NA. Stambuli JP. Hartwig JF. J. Am. Chem. Soc. 2001; 123: 4641
  • 17 Fernandes TA. Domingos JL. O. Rocha LI. A. Medeiros S. Nájera C. Costa PR. R. Eur. J. Org. Chem. 2014; 1314
    • 18a Malki F. Touati A. Rahal S. Moulay S. Asian J. Chem. 2011; 23: 961
    • 18b Niwayama S. Cho H. Lin C. Tetrahedron Lett. 2008; 49: 4434
    • 18c Niwayama S. J. Org. Chem. 2000; 65: 5834
  • 19 Luo M. Liu X. Zu Y. Fu Y. Zhang S. Yao L. Efferth T. Chem.-Biol. Interact. 2010; 188: 151
  • 20 Skouta R. Li CJ. Tetrahedron Lett. 2007; 48: 8343
  • 21 Baciocchi E. Dell’Aira D. Ruzziconi R. Tetrahedron Lett. 1986; 27: 2763
  • 22 Gandi VR. Lu Y. Chem. Commun. 2015; 16188
  • 23 Daikin Kogyo Co. Ltd. Jpn. Kokai Tokkyo Koho JP 59051251 A 19840324, 1984 ; Chem Abstr. 1984, 101, 72461
  • 24 Kamijo T. Tsubaki A. Yamaguchi T. Hirata K. Jpn. Kokai Tokkyo Koho JP 03024047 A 19910201, 1991 ; Chem Abstr. 1991, 115, 49430
  • 25 Jaita S. Phakhodee W. Pattarawarapan M. Synlett 2015; 26: 2006
  • 26 Al-Maharik N. Botting NP. Tetrahedron 2004; 60: 1637
  • 27 van Aardt TG. van Rensburg H. Ferreira D. Tetrahedron 2001; 57: 7113
  • 28 Chiba T. Akizawa T. Matsukawa M. Nishi M. Kawai N. Yoshioka M. Chem. Pharm. Bull. 1996; 44: 972
  • 29 Morton AA. Brachman AE. J. Am. Chem. Soc. 1954; 76: 2973
  • 30 Bernier D. Brückner R. Synthesis 2007; 2249
  • 31 Gray TI. Pelter A. Ward RS. Tetrahedron 1979; 35: 2539
  • 32 Shih TL. Ruiz-Sanchez J. Mrozik H. Tetrahedron Lett. 1987; 28: 6015
  • 33 Pinard E. Gaudry M. Hénot F. Thellend A. Tetrahedron Lett. 1998; 39: 2739
  • 34 Tseng K.-NT. Rizzi AM. Szymczak NK. J. Am. Chem. Soc. 2013; 135: 16352
  • 35 Neill KG. J. Chem. Soc. 1953; 3454

Zoom Image
Figure 1 Bioactive compounds with α-arylmalonate, phenylacetic and benzylnitrile moieties
Zoom Image
Figure 2 α-Arylmalonates, phenylacetic acid derivatives, and phenyl­acetonitriles synthesized in this work
Zoom Image
Scheme 1 α-Arylation reactions. Reagents and conditions: (i) Pd2(dba)3 (2.5% mol), tBu3PHBF4 (10% mol), K3PO4 (3 equiv), toluene, 20 h/70 °C (for 1ae); Na3PO4 (3 equiv), 15 h/70 °C (for 5ac).
Zoom Image
Scheme 2 Monohydrolysis of arylmalonates. Reagents and conditions: (i) KOH (2 equiv), MeOH/H2O (10:1, v/v), 36 °C, 2 h.
Zoom Image
Scheme 3 Hydrolysis/decarboxylation reactions. Reagents and conditions: For 3ae: (i) KOH (2 equiv), MeOH/H2O (10:1, v/v), 90 °C, 2.5 h; for 4ae: (ii) KOH (3 equiv), MeOH/H2O (10:1, v/v), 90 °C, 150 W, 20 min.
Zoom Image
Scheme 4 Hydrolysis/decarboxylation reactions. Reagents and conditions: (i) KOH (3 equiv), MeOH/H2O (10:1, v/v), 90 °C, 150 W, 20 min.