07-01-03 15:09
No 443851
      Phenethylamines via Heck Arylation of aryl iodides
(Rated as: excellent)

In Journal of Organic Chemistry  (1993),  58(12),  3299-303 ( phenethylamines are prepared from un(substituted) aryl iodides via Heck arylation in good yields.
This reaction is completely impractical but in Lego's eyes such a beauty that there is no reason to withhold it from the Hive.

Phenethylamines via Heck Arylation of a New Vinylamine Equivalent

A new vinylamine equivalent, N-vinyloxazolone 3, has been prepared in three steps and shown to undergo Heck arylation with a variety of substrates. The Heck adducts thus obtained are then converted in one step and high yield to phenethylamine hydrochlorides. As a general synthetic method for preparation of substituted phenethylamines, use of this new reagent is shown to be superior to N-vinylphthalimide in number of steps, regiospecificity, and chemical yield.

3-( 2-Chloroethyl)-4,5-diphenyl-2-(3H)oxazolone (1)
To 470 mL of DMF at rt was added 43.8 g of 2-chloroethylamine hydrochloride (378mmol,2 equiv), 31.8 g of NaHCO3 (378 mmol, 2 equiv), and 45.0 g of dioxolone 2 (189 mmol, 1 equiv) in the order given. After 18 h, the mixture was added to 800 mL of EtOAc, washed with 0.5 N HCl(2 x 500 mL), H2O (2 x 500 mL), and saturated NaCl(1 x 500 mL), and dried (Na2SO4, and the solvent were removed in vacuo. The residue was immediately dissolved in 225 mL of CF3CO2H (2.9 mol, 15 eq.,), allowed to stand for 2 h, and again evaporated to dryness. The residual oil was azeotroped with PhMe (2 x 500 mL) and swirled with warm hexane to cause rapid crystallization of the product. Recrystallization of this solid (hexane/EtOAc) gave 42.95 g of 1, and recrystallization of the mother liquors gave a further 9.66 g for a combined total of 52.61 g of 1, 93% yield, as a colorless crystalline solid, mp 101-102.5 C.

3-(2-Iodoethyl)-4,5-diphenyl-2(3H)oxazolone (2)
To a suspension of 201.8 g (1.319 mol, 7 eq.) of sodium iodide in 250 mL of NMP at 90 C was added 56.5 g (0.189 mol, 1 eq.) of chloride 1 over 10 min. After 3 h at 90 C, the reaction mixture was cooled to 0 C, diluted with 100 mL of H2O, and poured into 800 mL of cold H2O. After 20 min the slurry was filtered and the solid dried to give 71.5 g (97%) of iodide 2 as a colorless crystalline solid, mp 112-114 C.

3-Ethenyl-4,5-diphenyl-2(3H)oxazolone (3)
A solution of 71.0 g of iodide 2 (0.182 mol, 1 eq.) in 1 L of PhMe at 75 C was treatedwith 31.1 g of t-BuOK (0.247 mol, 1.36 eq.) in two portions at 15 min intervals. The suspension was heated under N2 for 1.5 h, cooled to rt, and added to 1 L of H2O in a separatory funnel.
The organic phase was washed with H2O (2 x 1 L), 0.1 N HCl (1 x 1 L), and saturated NaCl(1 x 1 L) and dried (Na2SO4), and the solvents were removed in vacuo to give 52 g of a yellow oil.
The oil was dissolved in 90 mL of MeOH, clouded with 10 mL of H2O, and scratched to cause rapid crystallization of 24.7 g (52%, first crop only) of pure N-vinyloxazolone 3 as a colorless crystalline solid, mp 95-97 C.

General Arylation Method A.
A mixture of 1.00 g of 1-chloro-4-iodobenzene (4.15 mmol, 1 eq.), 38 mg of Pd(OAc)2 (0.17 mmol, 0.04 eq.), 1.18 g of (n-Bu)4NCl hydrate (4.15 mmol, 1 eq.), 0.87 g of NaHCO3 (10.4 mmol, 2.5 eq.), 2.19 g of N-vinyloxazolone 1 (8.30 mmol, 2 eq.), and 20 mL of DMF was heated at 90 C for 48 h. The reaction mixture was cooled and diluted with 25 mL of H2O and the solid filtered. This solid was then chromatographed on silica gel (CH2Cl2) to give 0.977 g of oxazolone 16 (87 %) as a colorless crystalline solid, mp 196.5-197 C.

General Arylation Method B.
In a 30-mL stainless steel bomb were placed a flat stir bar, 0.39 g of NaOAc (4.70 mmol, 1.1 eq.), 1.24 g of oxazolone 3 (4.70 mmol, 1.1 eq.), 1.02 g of 4-iodoanisole (4.27 mmol, 1.0 eq.), 39 mg of Pd(OAc)2 (0.17 mmol, 0.04 eq.), 3 mL of DMF, and 1.5 mL of H2O in the order given. The bomb was sealed and heated in a 110 C oil bath behind a blast shield for 48 h. The bomb was cooled to 0 C, the contents were partitioned between EtOAc and H2O, and the aqueous fraction was reextracted with EtOAc. The organic layers were washed with H2O (2x) and saturated NaCl and dried (Na2SO4), and the solvents were removed in uacuo. The solid thus obtained was chromatographed on silica eluting with 1:1 CH2Cl2/Hex to give 0.716 g (45%) of pure 19 as a colorless crystalline solid, mp 171.5-172 C.

General Deprotection.

Oxazolone 17 (0.500 g, 1.41 mmol) was suspended in 20 mL of 95% EtOH + 4 mL of HOAc, and 150 mg of 10% Pd/C was added. The mixture was hydrogenated at 50 psi and 50 C for 3 h, 50 mg of additional 10% Pd/C was added, and the mixture was hydrogenated for 1 h further. TLC indicated only the presence of bisbenzyl and 2-(p-tolyl)ethylamine. The mixture was filtered through Solka-floc, and the solvents were removed in vacuo. The residue was azeotroped with PhMe (2 x 25 mL), dissolved in 10 mL of EtOH, and acidified with ethanolic HCl.
Excess EtOH was removed in vacuo and the residual solid suspended in 2 mL of EtOH and diluted with 25 mL of Et2O. The resultant white solid was fitered under a stream of N2 and dried to constant weight in a 70 C vacuum oven to give 210 mg of pure 2-(p-tolyl)ethylamine.HCl 25, 87 % yield, as a white solid. This material was identical (1H NMR, 13C NMR, IR, mp) with that obtained via addition of ethereal HCl to Aldrich 2-(p-tolyl)-ethylamine base.

Table I. Arylation of N-Vinyloxazolone 3 and Hydrogenation to Phenethylamines
entry iodide Heck adduct method: yield (%) amine yield (%)
1 Ph 13 A: 66   B: 66 21 96
2 2-FPh 14 A: 73   B: 54 22 88
3 3-FPh 15 A: 96   B: 75 23 80
4 4-ClPh 16 A: 87   B: 22 24 0a
5 4-MePh 17 A: 69   B: 69   C: 74 25 87
6 2-OMePh 18 A: 59   B: 41 26 86
7 4-OMePh 19 A: 58   B: 45 27 87
8 4-OHPh 20 A: 9   B: 42   C: 39 28 94

a 70% of 21 formed

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