3-Arylpropanoate Esters through the Palladium-Catalyzed Reaction of Aryl Halides with Acrolein Diethyl Acetal

Abstract

The reaction of aryl halides with acrolein diethyl acetal in the presence of Pd(OAc)₂, n-Bu₃N, and n-Bu₄NCl in DMF at 90 °C affords ethyl 3-arylpropanoates. A variety of functional groups are tolerated in the aryl halides, including ether, aldehyde, ketone, ester, nitrile, and nitro groups. ortho-Substituents do not hamper the reaction. 3-Arylpropanoate esters were isolated in good to excellent yields with many neutral, electron-rich and electron-poor aryl iodides and electron-poor aryl bromide. Neutral and electron-rich aryl bromides gave the desired ester in moderate yields.

palladium - alkenes - esters - aryl halides - Heck reaction

References

1 Zebovitz TC. Heck RF. J. Org. Chem.  1977,  42:  3907 

2 Battistuzzi G. Cacchi S. Fabrizi G. Org. Lett.  2003,  5:  777 

For related syntheses of α,β-unsaturated aldehydes based on the palladium-catalyzed reaction of aryl halides with a three carbon partner, see:

3a Patel BA. Kim J.-I. Bender DD. Kao L.-C. Heck RF. J. Org. Chem.  1981,  46:  1061 

3b Jeffery TJ. J. Chem. Soc., Chem. Commun.  1984,  1287 

3c Unroe MR. Reinhardt BA. Synthesis  1987,  981 

3d Parrain J.-L. Duchene A. Quintard J.-P. J. Chem. Soc., Perkin Trans. 1  1990,  187 

3e Phuan P.-W. Kozlowski MC. Tetrahedron Lett.  2001,  42:  3963 

For some recent references, see for example:

4a Mizojiri R. Urabe H. Sato F. J. Org. Chem.  2000,  65:  6217 

4b Shiina I. Imai Y. Suzuki M. Yanagisawa M. Mukaiyama T. Chem. Lett.  2000,  1062 

4c Svensson A. Fex T. Kihlberg J. J. Comb. Chem.  2000,  2:  736 

4d Takeda T. Takagi Y. Saeki N. Fujiwara T. Tetrahedron Lett.  2000,  41:  8377 

4e Fakhri SA. Yousefi BH. Tetrahedron  2000,  56:  8301 

4f Busch-Petersen J. Corey EJ. Tetrahedron Lett.  2000,  41:  2515 

4g Bulman P. Philip C. McKenzie MJ. Allin SM. Buckle DR. Tetrahedron  2000,  56:  9683 

4h Yang D. Wong M.-K. Yan Z. J. Org. Chem.  2000,  65:  4179 

4i Rahim MdA. Sasaki H. Saito J. Fujiwara T. Takeda T. Chem. Commun.  2001,  625 

4j Hess S. Dolker M. Haferburg D. Kertscher HP. Matysik F.-M. Ortwein J. Teubert U. Zimmermann W. Eger K. Pharmazie  2001,  56:  306 

4k Pouysegu L. Avellan A.-V. Quideau S. J. Org. Chem.  2002,  67:  3425 

4l Matsubara K. Iura T. Maki T. Nagashima H. J. Org. Chem.  2002,  67:  4985 

5a Brown TH. Blakemore RC. Durant GJ. Emmett JC. Ganellin CR. Parsons ME. Rawlings DA. Walker TF. Eur J. Med. Chem.  1988,  23:  53 

5b Misra RN. Brown BR. Han W.-C. Harris DN. Hedberg A. Webb ML. Steven EH. J. Med. Chem.  1991,  34:  2882 

5c Dickinson RP. Dack KN. Tute MS. Bioorg. Med. Chem. Lett.  1996,  6:  1691 

5d Nesloney CL. Kelly JW. J. Org. Chem.  1996,  61:  3127 

5e Molina P. Fresneda PM. Sanz MA. J. Org. Chem.  1999,  64:  2540 

5f Meyers MJ. Sun J. Carlson KE. Katzenellenbogen BS. Bioorg. Med. Chem. Lett.  1998,  8:  3589 

5g Katzenellenbogen JA. J. Med. Chem.  1999,  42:  2456 

5h Goldman S, Pennock GD, Morkin E, and Bahl JJ. inventors; PCT Int. Appl.  WO0260389.  ; Chem. Abstr. 2002, 137, 150233

6

Typical Procedure for the Preparation of Ethyl 3-Arylpropanoates ( 5). To a solution of 2-iodo-4-nitrotoluene (0.132 g, 0.501 mmol), acrolein diethylacetal (0.229 mL, 1.50 mmol), n-Bu₄NCl (0.139 g, 0.50 mmol), n-Bu₃N (0.238 mL, 1.00 mmol) in 2.0 mL of DMF, Pd(OAc)₂ (0.003 g, 0.015 mmol) was added. The mixture was warmed at 90 °C and stirred for 1 h. After cooling, the reaction mixture was diluted with 2 N HCl and extracted with Et₂O. The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by chromatography (n-hexane/EtOAc 85/15 v/v) to give 0.109 g of 5z (92% yield) as an oil. IR (KBr): 1733, 1521, 1348 cm^-1. ¹H NMR (CDCl₃): δ = 8.01 (d, J ₁ = 2.3 Hz, 1 H), 7.95 (dd, J ₁ = 8.3 Hz, J ₂ = 2.4 Hz, 1 H), 7.28 (d, J = 8.3 Hz, 1 H), 4.14 (q, J ₁ = 7.1 Hz, 2 H), 3.01 (t, J ₁ = 7.5 Hz, 2 H), 2.64 (t, J ₁ = 7.5 Hz, 2 H), 2.42 (s, 3 H), 1.24 (t, J ₁ = 7.1 Hz, 3 H). ¹³C NMR (CDCl₃): δ = 172.3, 146.5, 144.2, 140.3, 131.0, 123.2, 121.4, 60.7, 33.9, 28.0, 19.6, 14.1. MS: m/z (%) = 237 (55) [M⁺], 192 (70), 191 (53), 164 (78), 150 (100), 91(95). Anal. Calcd for C₁₂H₁₅NO₄: C, 70.65; H, 6.37; N, 5.90. Found: C, 70.61; H, 6.34; N, 5.95.

7

Compound 6i was prepared according to the ref. [2] , omitting treatment with HCl.

8

Diiodobenzene (0.5 mmol), acrolein diethyl acetal (3 mmol), Pd(OAc)₂ (6 mol%), n-Bu₃N (2 mmol), n-Bu₄NCl (1.5 mmol), DMF (1 mL).
3-[2-(2-Ethoxycarbonyl-ethyl)-phenyl]-propionic Acid Ethyl Ester ( 8a). Oil. IR (neat): 1734 cm^-1. ¹H NMR (CDCl₃): δ = 7.17 (s, 4 H), 4.15 (q, J ₁ = 7.1 Hz, 4 H), 2.99 (t, J = 7.7 Hz, 4 H), 2.62 (t, J ₁ = 7.7 Hz, 4 H), 1.26 (t, J ₁ = 7.1, Hz, 6 H). ¹³C NMR (CDCl₃): δ = 172.9, 138.4, 129.1, 126.7, 60.6, 35.4, 27.6, 14.3. MS: m/z (%) = 278 (16) [M⁺], 233 (34), 186 (90), 158 (100), 144 (34), 130 (64), 117 (91). Anal Calcd for C₁₆H₂₂O₄: C, 69.04; H, 7.97. Found: C, 69.11; H, 7.94.
3-[4-(2-Ethoxycarbonyl-ethyl)-phenyl]-propionic Acid Ethyl Ester ( 8b). Mp 65-66 °C. IR (KBr): 1725 cm^-1. ¹H NMR (CDCl₃): δ = 7.13 (s, 4 H), 4.13 (q, J ₁ = 7.2 Hz, 4 H), 2.92 (t, J = 8.0 Hz, 4 H), 2.60 (t, J ₁ = 8.0 Hz, 4 H), 1.25 (t, J ₁ = 7.2, Hz, 6 H). ¹³C NMR (CDCl₃): δ = 173.0, 138.5, 128.5, 60.5, 36.0, 30.6, 14.3. MS: m/z (%) = 278 (24) [M⁺], 233 (10), 204 (60), 190 (27), 159 (16), 130 (57), 117 (100). Anal. Calcd for C₁₆H₂₂O₄: C, 69.04; H, 7.97. Found: C, 69.09; H, 7.93.

For palladium-catalyzed coupling of aryl halides, see for example:

9a Organozinc compounds: Tamaru Y. Ochiai H. Nakamura T. Yoshida Z. Tetrahedron Lett.  1986,  27:  955 

9b See also: Nakamura E. Aoki S. Sekyia K. Oshino H. Kuwajima I. J. Am. Chem. Soc.  1987,  109:  8056 

9c 1-Tributylstannyl-3,3-diethoxyprop-1-ene: Parrain J.-L. Duchene A. Quintard J.-P. J. Chem. Soc., Perkin Trans. 1  1990,  187 

9d Alkyltrifluorosilanes: Matsuhashi H. Kuroboshi M. Hatanaka Y. Hiyama T. Tetrahedron Lett.  1994,  35:  6507 

10 For nickel-catalyzed coupling of alkyl iodides, see for example: Arylzinc compounds: Giovannini R. Knochel P. J. Am. Chem. Soc.  1998,  120:  11186 

11 For the nickel-catalyzed reaction of organic halides with olefins in the presence of zinc, see for example: Sustmann R. Hopp P. Holl P. Tetrahedron Lett.  1989,  30:  689 

For electrochemical methods involving aryl halides and transition metal catalysis, see for example:

12a Condon-Gueugnot S. Léonel E. Nédélec J.-Y. Périchon J. J. Org. Chem.  1995,  60:  7684 

12b Kurono N. Sugita K. Takasugi S. Tokuda M. Tetrahedron  1999,  55:  6097 

12c Gomes P. Gosmini C. Nédélec J.-Y. Périchon J. Tetrahedron Lett.  2002,  43:  5901 

For recent references on the synthesis of 3-aryl propanoate esters via reduction of cinnamate esters, see:

13a Taylor RA. Santora BP. Gagne MR. Org. Lett.  2000,  2:  1781 

13b Chauhan M. Boudjouk P. Can. J. Chem.  2000,  78:  1396 

13c Couturier M. Andresen BM. Tucker JL. Dube P. Brenek SJ. Negri JT. Tetrahedron Lett.  2001,  42:  2763 

13d Vinson SL. Gagne MR. Chem. Commun.  2001,  1130 

13e Desai B. Danks TN. Tetrahedron Lett.  2001,  42:  5963 

13f Shibata I. Suwa T. Ryu K. Baba A. J. Org. Chem.  2001,  66:  8690 

13g Concellon JM. Rodriguez-Solla H. Chem.-Eur. J.  2001,  7:  4266 

13h Basu MK. Samajdar S. Becker FF. Banik BK. Synlett  2002,  319 

13i Bremeyer NB. Ley SV. Ramarao C. Shirley IM. Smith SC. Synlett  2002,  1843