Archives of Natural and Medicinal Chemistry (ISSN: 2577-0195)

Article / brief report

"A Simple Metal-Ligand Catalyzed Heck-Type Reaction for β, β-Doublearylation of Acrylic Acid Esters"

Benjamin Wolff, Franz-Josef Meyer-Almes*

Department of Chemical Engineering and Biotechnology, University of Applied Sciences, Germany

*Corresponding Author: Franz-Josef Meyer-Almes, Department of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Germany. Tel: +496151168406; Fax: +496151168404; Email: franz-josef.meyer-almes@h-da.de;

Received Date: 22 December, 2017; Accepted Date: 05 February, 2018; Published Date: 12 February, 2018

1.                   Introduction

As a part of Pd-catalyzed reactions the Heck-Mizoroki reaction has a huge significance in R&D of pharmaceuticals [1]. Since the very first steps in the discovery of this reaction type, double arylation of acrylic esters have been known, but just recently investigated in greater detail. In most cases β,β-diarylated acrylates were obtained under demanding conditions such as high pressure [2], special metal-ligand systems [3], ionic liquids [4] or special auxiliary reactants [5]. Double arylation has also been observed in microwave reactions [6]. By using propenols as starting material double arylation could be achieved in a domino Heck isomerization/Saegusa/Heck reaction resulting in β,β-diarylated propenals [7]. Yet no study focused on the basic conditions that were already used in the very first years after discovering this reaction type. Going back to its origins, we developed a simple and straightforward procedure that uses a basic metal-ligand system to synthesize β,β-diarylated acrylates and gives access to a pharmaceutical interesting class of products that is usually received under harsh conditions and in bad yields.

2.                   Keywords: Alkenes; Catalysis; One-pot Synthesis

1.                   General Procedure

Methyl acrylate (600 mg, 6.97 mmol), aryl iodide (27.9 mmol, 4 eq), potassium carbonate (2.12g, 15.3 mmol), palladium acetate (78.2 mg, 348 µmol) and tri-o-tolylphosphine (212 mg, 697µmol) are dissolved in dimethylformamide (5 ml) and stirred for 3 hours at 70°C. Then the mixture is stirred for 72 hours at 110°C. Ethyl acetate (30 ml) is added, the solution washed with brine (15 ml) and water (15 ml) and the organic layer is dried with sodium thiosulfate. The solvent is removed under reduced pressure and the product is obtained after column chromatography on silica gel (hexane/ethylacetate 20:1 v/v).

3.1.              3,3-Di-p-tolylmethylacrylate (2a)

Yield: 562.7 mg, yellow oil

1H-NMR (500 MHz, CDCl3): δ = 7.23 (dd, J = 8.0, 3.9 Hz, 4H), 7.15 (dd, J = 7.7, 5.6 Hz, 4H),6.35 (s, 1H), 3.65 (s, 3H), 2.43 (s, 3H), 2.39 (s, 3H).

13C-NMR (126 MHz, CDCl3): δ = 166.62 (s), 157.43 (s), 139.70 (s), 138.40 (s), 138.04 (s),136.05 (s), 129.25 (s), 129.14 (s), 128.64 (s), 128.43 (s), 115.66 (s), 51.19 (s), 21.47 (s), 21.30 (s).

MS (70 eV, EI): m/z (%) = 266.1 (100), 235.1 (98), 219.1 (6), 207.1 (26), 191.1 (40), 178.1 (13), 165.1 (18), 119.1 (33), 91.1 (13)

3.2.              3,3-Di-m-tolylmethylacrylate (2b)

Yield: 527.4 mg, colourless oil.

1H-NMR (500 MHz, CDCl3): δ = 7.38 – 7.27 (m, 1H), 7.26 – 7.14 (m, 4H), 7.08 (dd, J = 24.4,7.5 Hz, 2H), 7.03 (s, 1H), 6.36 (s, 1H), 3.64 (s, 3H), 2.38 (s, 3H), 2.35 (s, 3H).

13C-NMR (126 MHz, CDCl3): δ = 166.54 (s), 157.50 (s), 145.12 (s), 141.08 (s), 138.94 (s),138.06 (s), 137.46 (s), 131.20 (s), 130.27 (s), 129.66 (s), 129.02 (s), 128.92 (s), 128.32 (s),127.77 (s), 126.36 (s), 125.71 (s), 116.71 (s), 51.25 (s), 21.53 (s), 21.47 (s).

MS (70 eV, EI): m/z (%) = 266.1 (94), 235.1 (100), 219.1 (9), 207.1 (62), 192.1 (53), 178.1(16), 165.1 (24), 115.1 (38), 89.1 (14)

3.3.              3,3-Di-o-tolylmethylacrylate (2c)

Yield: 134 mg, colourless oil.

1H-NMR (500 MHz, CDCl3): δ = 7.32 – 7.13 (m, 8H), 6.21 (s, 1H), 3.67 (s, 3H), 2.40 (s, 3H),2.22 (s, 3H).

13C-NMR (126 MHz, CDCl3): δ = 166.20 (s), 156.83 (s), 140.80 (s), 139.42 (s), 135.77 (s),135.60 (s), 131.30 (s), 130.18 (s), 129.92 (s), 129.21 (s), 128.45 (s), 128.05 (s), 125.86 (s),125.33 (s), 121.64 (s), 51.35 (s), 20.93 (s), 19.96 (s).

MS (70 eV, EI): m/z (%) = 266.1 (12), 251.1 (42), 235.1 (100), 219.1 (19), 205.1 (41), 191.1(99), 178.1 (45), 165.1 (28), 115.1 (55), 91.1 (23)

3.4.              3,3-Bis(4-methoxyphenyl) methylacrylate (2d)

Yield: 868.4 mg, yellow oil.

1H-NMR (500 MHz, CDCl3): δ = 7.28 – 7.23 (m, 2H), 7.19 – 7.14 (m, 2H), 6.95 – 6.89 (m,2H), 6.88 – 6.82 (m, 2H), 6.25 (s, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 3.63 (s, 3H).

13C-NMR (126 MHz, CDCl3): δ = 166.73 (s), 160.85 (s), 159.76 (s), 156.85 (s), 133.84 (s),130.90 (s), 130.03 (s), 114.30 (s), 113.76 (s), 113.26 (s), 55.33 (s), 55.19 (s), 51.09 (s).

MS (70 eV, EI): m/z (%) = 298.1 (100), 267.1 (59), 240.1 (17), 225.1 (27), 209.1 (10), 195.1(8), 181.1 (10), 165.1 (15), 152.1 (26), 135.1 (51)

3.5.               3,3-Bis(3-methoxyphenyl) methylacrylate (2e)

For this derivate 300 mg (3.48 mmol) of methyl acrylate were used as educt.

Yield: 234 mg, yellow oil.

1H-NMR (500 MHz, CDCl3): δ = 7.32 – 7.28 (m, 1H), 7.24 (t, J = 8.0 Hz, 1H), 6.93 (dd, J =2.6, 0.9 Hz, 1H), 6.92 – 6.89 (m, 2H), 6.87 – 6.84 (m, 1H), 6.83 – 6.80 (m, 1H), 6.76 (dd, J =2.5, 1.6 Hz, 1H), 6.37 (s, 1H), 3.79 (s, 3H), 3.77 (s, 3H), 3.62 (s, 3H).

13C-NMR (126 MHz, CDCl3): δ = 166.38 (s), 159.64 (s), 159.29 (s), 156.48 (s), 142.11 (s),140.16 (s), 129.42 (s), 128.99 (s), 121.65 (s), 120.93 (s), 117.22 (s), 114.95 (s), 114.78 (s),114.07 (s), 113.80 (s), 55.36 (s), 55.29 (s), 51.35 (s).

MS (70 eV, EI): m/z (%) = 300.1 (3), 298.1 (100), 267.1 (71), 239.1 (59), 224.1 (24), 208.1(11), 195.1 (11), 181.1 (16), 165.1 (27), 152.1 (33), 135.1 (21)

3.6.              3,3-Bis(4-chlorophenyl) methylacrylate (2f)

Yield: 898 mg, yellow solid.

1H-NMR (500 MHz, CDCl3): δ = 7.36 (d, J = 8.6 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 7.19 (d, J= 8.8 Hz, 2H), 7.13 (d, J = 8.6 Hz, 2H), 6.33 (s, 1H), 3.62 (s, 3H).

MS (70 eV, EI): m/z (%) = 309.0 (9), 308.0 (45), 306.0 (68), 277.0 (65), 275.0 (100), 247.0 (20), 212.0 (78), 176.1 (70), 139.0 (24)

3.7.              3,3-Bis(3-chlorophenyl) methylacrylate (2g)

Yield: 433 mg, yellow oil.

1H-NMR (500 MHz, CDCl3): δ = 7.38 (ddd, J = 8.1, 2.0, 1.3 Hz, 1H), 7.35 (ddd, J = 7.4, 2.2,1.1 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.27 (t, J = 7.9 Hz, 1H), 7.27 (t, J = 4.6 Hz, 1H), 7.19 (t, J = 1.7 Hz, 1H), 7.17 – 7.13 (m, 1H), 7.10 (dt, J = 7.4, 1.4 Hz, 1H), 6.37 (s, 1H), 3.64 (s, 3H).

13C-NMR (126 MHz, CDCl3): δ = 165.80 (s), 153.89 (s), 142.08 (s), 139.96 (s), 134.80 (s),134.20 (s), 129.89 (s), 129.78 (s), 129.46 (s), 129.12 (s), 128.72 (s), 128.24 (s), 127.41 (s),126.49 (s), 118.82 (s), 51.59 (s), 31.70 (s), 22.77 (s), 14.22 (s).

MS (70 eV, EI): m/z (%) = 309.0 (10), 308.0 (44), 306.0 (67), 277.0 (66), 275.0 (100), 247.0 (35), 212.0 (97), 176.1 (87), 139.0 (16)

3.8.              3,3-Bis(4-fluorophenyl) methylacrylate (2h)

Yield: 167 mg, yellow solid.

1H-NMR (500 MHz, CDCl3): δ = 7.26 (dd, J = 9.0, 5.3 Hz, 2H), 7.18 (dd, J = 8.8, 5.4 Hz, 2H),7.08 (t, J = 8.7 Hz, 2H), 7.02 (t, J = 8.7 Hz, 2H), 6.31 (s, 1H), 3.62 (s, 3H).

13C-NMR (126 MHz, CDCl3): δ = 166.27 (s), 164.75 (s), 163.92 (s), 162.75 (s), 161.95 (s),155.04 (s), 143.64 (s), 136.99 (d, J = 2.9 Hz), 134.50 (d, J = 3.2 Hz), 131.21 (s), 131.15 (s),130.34 (s), 130.28 (s), 130.08 (s), 130.01 (s), 117.06 (s), 115.72 (s), 115.54 (s), 115.28 (s),115.11 (s), 51.41 (s).

MS (70 eV, EI): m/z (%) = 274.1 (77), 243.1 (100), 214.1 (72), 194.1 (30), 175.1 (15), 123.0 (27)

3.9.              3,3-Di(naphthalene-1-yl) methylacrylate (2i)

Yield: 164 mg, yellow oil.

1H-NMR (500 MHz, CDCl3): δ = 8.52 (dd, J = 8.3, 0.7 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.96 – 7.85 (m, 3H), 7.82 (dd, J = 5.9, 3.4 Hz, 1H), 7.60 – 7.51 (m, 2H), 7.50 – 7.45 (m, 2H), 7.45 – 7.39 (m, 2H), 7.38 – 7.33 (m, 2H), 6.64 (s, 1H), 3.50 (s, 3H).

13C-NMR (126 MHz, CDCl3): δ = 166.10 (s), 153.58 (s), 139.57 (s), 138.36 (s), 134.31 (s),133.70 (s), 131.42 (s), 130.87 (s), 129.22 (s), 128.86 (s), 128.67 (s), 128.61 (s), 127.25 (s),126.98 (s), 126.58 (s), 126.46 (s), 126.08 (s), 125.85 (s), 125.31 (s), 125.22 (s), 125.18 (s),125.11 (s), 124.36 (s), 60.47 (s), 51.41 (s), 21.13 (s), 14.31 (s).

MS (70 eV, EI): m/z (%) = 338.1 (19), 305.1 (12), 278.1 (100), 263.1 (11), 210.1 (23), 179.0(10), 152.1 (10), 138.1 (26)

3.10.           3,3-Bis(3,4-dimethylphenyl) methylacrylate (2j)

Yield: 90.5 mg, yellow oil.

1H-NMR (500 MHz, CDCl3): δ = 7.17 (d, J = 7.6 Hz, 1H), 7.13 (s, 1H), 7.10 (d, J = 7.9 Hz,1H), 7.04 (dd, J = 7.9, 1.8 Hz, 1H), 6.99 (dd, J = 10.3, 2.6 Hz, 2H), 6.31 (s, 1H), 3.64 (s, 3H),2.33 (s, 3H), 2.29 (s, 2H), 2.28 (s, 3H), 2.26 (s, 2H).

13C-NMR (126 MHz, CDCl3): δ = 166.73 (s), 157.84 (s), 139.01 (s), 138.37 (s), 136.64 (s),136.59 (s), 136.53 (s), 135.97 (s), 130.34 (s), 129.69 (s), 129.54 (s), 129.16 (s), 126.91 (s),126.24 (s), 115.50 (s), 51.19 (s), 31.71 (s), 22.77 (s), 19.87 (s), 19.79 (s), 19.68 (s), 14.21 (s).

MS (70 eV, EI): m/z (%) = 294.2 (100), 263.1 (81), 235.1 (25), 220.1 (29), 205.1 (25), 189.1(19), 133.1 (34)

4.       Results and Discussion

This paper reports a simple metal-ligand catalyzed way to generate β,β-diarylated acrylic acids from standard chemicals. Moreno-Mañas, et al. showed the double arylation of ethyl cinnamates using similar conditions and a phase-transfer catalyst [8]. Unfortunately, this study only produced asymmetric ethyl 3-aryl-3-phenyl propenoates with para-substituted aryls. To get a wider view on this reaction, we varied the position of the substitutes and generated symmetric 3,3-diarylic esters. While usual ways to generate diarylated acrylic acids need complex ligands for the palladium, we used tri(o-tolyl) phosphine as ligand. As base potassium carbonate showed to have the best results yield-wise. The reaction was carried out in dimethylformamide and stirred for 3 days at 110 °C. The aryl iodides were used in excess and the unreacted aryl iodides were retrieved from the reaction mixture. The results are listed in (Table 1).

The highest yields were achieved by using methyl acrylic esters, benzyl and tert-butyl esters did only produce the monoarylated products. The equivalents for the aryl halides were raised from 2 equivalents up to 4 equivalents, where no yield improvement was observed above this amount. Potassium carbonate proved to be a better choice for the base than trimethylamine and tri(o-tolyl) phosphine showed to be the ligand of choice in comparison to triphenylphosphine and dppe.

Electron deficient aryl halides such as iodopyridin or 3-chloro-4-iodobenzotrifuoride only delivered the monoarylated product. Depending on the substitution pattern, the yield was highest for para-substituted and lowest for ortho-substituted aryl halides. Most ortho-substituted aryl halides only produced the monoarylated product.



 

Entry

 

 

Aryl iodide

 

 

Product

 

Yield(%)

1

4-MeC6H4I

2a

30

2

3-MeC6H4I

 

2b

28

3

2-MeC6H4I

 

2c

7

4

4-MeOC6H4I

 

2d

42

5

3-MeOC6H4I

 

2e

23

6

4-ClC6H4I

 

2f

8

7

3-ClC6H4I

 

2g

20

8

4-FC6H4I

 

2h

9

9

C10H7I

 

2i

7

10

3,4-Me2C6H3I

 

2j

4

 

Table 1: Doublearylation of acrylic esters via Heck reaction.

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2.       Sugihara T, Takebayashi V, Kaneko C (1995) Effects of high pressure on the heck reaction. Is it possible to control dehydropalladation of alkylpalladium intermediates having β-hydrogens? Tetrahedron Letters 36: 5547-5550.

3.       Luis Botella, Carmen N Ajera (2004) Controlled mono and double Heck reactions in water catalyzed by an oxime-derived palladacycle. Tetrahedron Letters 45: 1833-1836.

4.       Guang-Rong Peh, Eric Assen B Kantchev, Chi Zhang, Jackie Y Ying (2009) N-heterocycle carbene (NHC)-ligated cyclopalladated N, N-dimethylbenzylamine: a highly active, practical and versatile catalyst for the Heck-Mizoroki reaction. Org Biomol Chem 7: 2110-2119.

5.       Vallin KS, Emilsson P, Larhed M, Hallberg AV. Calo, et al. (2001) Heck reaction of β-substituted acrylates in ionic liquids catalyzed by a Pd-benzothiazole carbene complex. Tetrahedron 57: 6071-6077.

6.       Delample M, Nicolas Villandier, Jean-Paul Douliez, S´everine Camy, Jean-Stephane Condoret, et al. (2010) Glycerol as a cheap, safe and sustainable solvent for the catalytic and regioselective β,β-diarylation of acrylates over palladium nanoparticles Green Chem 12: 804-808.

7.       Karl S Vallin, Per Emilsson, Mats Larhed, Anders Hallberg (2002) High-Speed Heck Reactions in Ionic Liquid with Controlled Microwave Heating. J Org Chem 67: 6243-6246.

8.       Zhi-Qiang Zhu, Jian-Shi He, Hai-Jun Wang, Zhi-Zhen Huang (2015) Domino Reactions Containing Different Types of Heck Reactions for Selective 3,3- and 1,3-Diarylations of Propenol with Aryl Halides by Triple Catalysis. J Org Chem 80: 9354-9359.

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Citation: Wolff B, Meyer-Almes FJ (2018) A Simple Metal-Ligand Catalyzed Heck-Type Reaction for β,β-Doublearylation of Acrylic Acid Esters. Arch Nat Med Chem: ANMC-112. DOI:10.29011/ANMC-112.000012

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