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All 2 posts Subject: Reduction of an aldoxime with Zn/HCl Please login to post Down

Lego
(Newbee)
06-26-03 14:55
No 442691
User Picture       Reduction of an aldoxime with Zn/HCl
(Rated as: excellent)

Tetrahedron, 2002, 58(8), 1513-1518 (http://www.angelfire.com/scifi2/lego/journals/9.pdf)
DOI:10.1016/S0040-4020(01)01235-2

The authors prepare 3-hydroxy-4-methoxy-5-bromo-phenethylamine 6 from 2-bromo-isovaniline. In this paper two ways to get the desired product are used.

The classic way:
Nitrostyrene formation and reduction with LAH

The alternative way:
Homologation of the benzaldehyde to phenylacetaldehyde, preparation of the oxime and reduction of the oxime to the PEA. The last step is most interesting as it uses Zn/HCl to get the pure amine in 71% yield.

The alternative way:

4-Bromo-2-methoxy-5-(2-methoxyethenyl)phenol (3)
To a stirred solution of methoxymethyltriphenylphosphonium bromide (44.51 g, 129.8 mmol) in anhydrous THF (250 ml) KOtBu (30.35 g, 270.5 mmol) was added at 0°C within 30 min and stirred for 30 min at this temperature. 2-Bromo-5-hydroxy-4-methoxybenzaldehyde (25.0 g, 108.2 mmol) was added within 30 min, stirred for 5 h at rt and hydroxylyed with water (100 ml). The solvent was removed in vacuo, and the residue was acidified with 2N HCl and extracted with EtOAc (3x150 ml). The combined organic layers were washed with water (2x200 ml) and brine (200 ml), dried (Na₂SO₄), filtered and concentrated. The residue was purified by MPLC (450 g SiO₂, hexane/EtOAc=4:1) to yield 3 as colorless crystals (27.2 g, 97%).

2-Bromo-5-hydroxy-4-methoxybenzeneacetaldehyde (4)
3 (5.90 g, 22.6 mmol) in THF (50 ml)/2N HCl (8 ml) was stirred under reflux 2.5 h. Water (50 ml) was added, and the solution was concentrated in vacuo to a volume of 45 ml. The residue was extracted with EtOAc (3x80 ml), the combined organic layers were washed with water (2x100 ml), saturated NaHCO₃ (2x100 ml) and brine (1x100 ml), dried (Na₂SO₄), filtered and evaporated in vacuo to yield 4 as colorless crystals (5.40 g, 97%).

2-Bromo-5-hydroxy-4-methoxybenzeneacetaldehyde oxime (7)
4 (1.98 g, 8.08 mmol) , triethylamine (2.04 g, 20.2 mmol) and hydroxylamine hydrochloride (1.12 g, 16.2 mmol) in EtOH (30 ml) were refluxed for 2 h. The solvent was removed in vacuo, and the residue was partitioned between 2N HCl (50 ml) and EtOAc (50 ml). The aqueous layer was extracted with EtOAc (2x15 ml), and the combined organic layers were washed with 2N HCl (2x50 ml), water (2x50 ml), saturated NaHCO₃ (2x50 ml) and brine (1x50 ml), dried (Na₂SO₄), filtered and concentrated. The residue was triturated with cold chloroform (3 ml) to yield 7 as colorless crystals. (2.0 g, 95%).

Method C: To a solution of 7 in THF (20 ml)/2N HCl (8 ml) zinc (1.0, 15.3 mmol) was added and refluxed for 24 h. The suspension was filtered and concentrated in vacuo to a volume of 6 ml. This aqueous layer was washed with chloroform (2x4 ml), the pH was adjusted to >10 with conc. NH₃ and the aqueous layer was extracted with chloroform (3x5 ml). The combined organic layers were washed with water (2x10 ml) and brine (20 ml), dried (Na₂SO₄), filtered and evaporated to yield 6 as colorless crystals (135 mg, 71%). NMR data identical to the produti obtained using Method A

Method A is the 'classic' way from the benzaldehyde with nitromethan/ammonium acetate (92%) and reduction with lithium aluminium hydride (61%).

The 'classic' method needs two steps with an overall yield of 56%, the 'alternative' way yields 63%.

Molecule: A ("c1(c(cc(c(c1)O)OC)Br)C=O")
Molecule: 3 ("c1(c(cc(c(c1)O)OC)Br)/C=C/OC")
3
Molecule: 4 ("c1(c(cc(c(c1)O)OC)Br)CC=O")
4
Molecule: 7 ("c1(c(cc(c(c1)O)OC)Br)C/C=N/O")
7
Molecule: 6 ("c1(c(cc(c(c1)O)OC)Br)CCN")
6

The homologation of the benzaldehyde is expensive compared to nitromethane but the reduction of the aldoxime with Zn/HCl offers an alternative to other reductions methods.

The candle that burns twice as bright burns half as long

Rhodium
(Chief Bee)
06-26-03 15:14
No 442693
User Picture       Phenethylamines via phenylacetaldehydes

Very interesting novel method - the phenylacetaldehyde can be made much more cheaply using the Darzen condensation with methyl chlorocacetate: https://www.rhodium.ws/chemistry/2ch.darzen.html

A related homologation can be found in Post 338923 (Rhodium: "Substituted benzaldehydes to phenethylalcohols", Serious Chemistry) - Lewis acid catalyzed rearrangement (with LiI or BF₃.Et₂O etc.) of the intermediate epoxide would yield the phenylacetaldehyde instead.

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	All 2 posts		Subject: Reduction of an aldoxime with Zn/HCl		Please login to post		Down


		Lego (Newbee) 06-26-03 14:55 No 442691				Reduction of an aldoxime with Zn/HCl (Rated as: excellent)
						Tetrahedron, 2002, 58(8), 1513-1518 (http://www.angelfire.com/scifi2/lego/journals/9.pdf) DOI:10.1016/S0040-4020(01)01235-2 The authors prepare 3-hydroxy-4-methoxy-5-bromo-phenethylamine 6 from 2-bromo-isovaniline. In this paper two ways to get the desired product are used. The classic way: Nitrostyrene formation and reduction with LAH The alternative way: Homologation of the benzaldehyde to phenylacetaldehyde, preparation of the oxime and reduction of the oxime to the PEA. The last step is most interesting as it uses Zn/HCl to get the pure amine in 71% yield. The alternative way: 4-Bromo-2-methoxy-5-(2-methoxyethenyl)phenol (3) To a stirred solution of methoxymethyltriphenylphosphonium bromide (44.51 g, 129.8 mmol) in anhydrous THF (250 ml) KOtBu (30.35 g, 270.5 mmol) was added at 0°C within 30 min and stirred for 30 min at this temperature. 2-Bromo-5-hydroxy-4-methoxybenzaldehyde (25.0 g, 108.2 mmol) was added within 30 min, stirred for 5 h at rt and hydroxylyed with water (100 ml). The solvent was removed in vacuo, and the residue was acidified with 2N HCl and extracted with EtOAc (3x150 ml). The combined organic layers were washed with water (2x200 ml) and brine (200 ml), dried (Na₂SO₄), filtered and concentrated. The residue was purified by MPLC (450 g SiO₂, hexane/EtOAc=4:1) to yield 3 as colorless crystals (27.2 g, 97%). 2-Bromo-5-hydroxy-4-methoxybenzeneacetaldehyde (4) 3 (5.90 g, 22.6 mmol) in THF (50 ml)/2N HCl (8 ml) was stirred under reflux 2.5 h. Water (50 ml) was added, and the solution was concentrated in vacuo to a volume of 45 ml. The residue was extracted with EtOAc (3x80 ml), the combined organic layers were washed with water (2x100 ml), saturated NaHCO₃ (2x100 ml) and brine (1x100 ml), dried (Na₂SO₄), filtered and evaporated in vacuo to yield 4 as colorless crystals (5.40 g, 97%). 2-Bromo-5-hydroxy-4-methoxybenzeneacetaldehyde oxime (7) 4 (1.98 g, 8.08 mmol) , triethylamine (2.04 g, 20.2 mmol) and hydroxylamine hydrochloride (1.12 g, 16.2 mmol) in EtOH (30 ml) were refluxed for 2 h. The solvent was removed in vacuo, and the residue was partitioned between 2N HCl (50 ml) and EtOAc (50 ml). The aqueous layer was extracted with EtOAc (2x15 ml), and the combined organic layers were washed with 2N HCl (2x50 ml), water (2x50 ml), saturated NaHCO₃ (2x50 ml) and brine (1x50 ml), dried (Na₂SO₄), filtered and concentrated. The residue was triturated with cold chloroform (3 ml) to yield 7 as colorless crystals. (2.0 g, 95%). Method C: To a solution of 7 in THF (20 ml)/2N HCl (8 ml) zinc (1.0, 15.3 mmol) was added and refluxed for 24 h. The suspension was filtered and concentrated in vacuo to a volume of 6 ml. This aqueous layer was washed with chloroform (2x4 ml), the pH was adjusted to >10 with conc. NH₃ and the aqueous layer was extracted with chloroform (3x5 ml). The combined organic layers were washed with water (2x10 ml) and brine (20 ml), dried (Na₂SO₄), filtered and evaporated to yield 6 as colorless crystals (135 mg, 71%). NMR data identical to the produti obtained using Method A Method A is the 'classic' way from the benzaldehyde with nitromethan/ammonium acetate (92%) and reduction with lithium aluminium hydride (61%). The 'classic' method needs two steps with an overall yield of 56%, the 'alternative' way yields 63%. Molecule: A ("c1(c(cc(c(c1)O)OC)Br)C=O") Molecule: 3 ("c1(c(cc(c(c1)O)OC)Br)/C=C/OC") 3 Molecule: 4 ("c1(c(cc(c(c1)O)OC)Br)CC=O") 4 Molecule: 7 ("c1(c(cc(c(c1)O)OC)Br)C/C=N/O") 7 Molecule: 6 ("c1(c(cc(c(c1)O)OC)Br)CCN") 6 The homologation of the benzaldehyde is expensive compared to nitromethane but the reduction of the aldoxime with Zn/HCl offers an alternative to other reductions methods. The candle that burns twice as bright burns half as long



		Rhodium (Chief Bee) 06-26-03 15:14 No 442693				Phenethylamines via phenylacetaldehydes
						Very interesting novel method - the phenylacetaldehyde can be made much more cheaply using the Darzen condensation with methyl chlorocacetate: https://www.rhodium.ws/chemistry/2ch.darzen.html A related homologation can be found in Post 338923 (Rhodium: "Substituted benzaldehydes to phenethylalcohols", Serious Chemistry) - Lewis acid catalyzed rearrangement (with LiI or BF₃.Et₂O etc.) of the intermediate epoxide would yield the phenylacetaldehyde instead.

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