Hive Serious Chemistry

	Main Index Search Register Login Who's Online FAQ Links
	Main Index Search Register Login Who's Online FAQ Links

	3 Online, 0 Active		You are not logged in

This is a historical archiveThe forum is read-only. Private information has been removed. It is not possible to login.

	Serious Chemistry	Thread: Previous Forum index Next

All 3 posts Subject: Grignard Synthesis of Chiral Amphetamines Please login to post Down

Rhodium
(Chief Bee)
05-31-04 17:15
No 510550
User Picture       Grignard Synthesis of Chiral Amphetamines
(Rated as: good read)

_{Asymmetric α-Substituted Phenethylamines. V.}
Synthesis of Chiral 1-Alkyl-2-phenylethylamines via Grignard Reaction of 4-Phenyl-1,3-oxazolidines
Hiroshi Takahashi,Yasuhiro Chida, Kimio Higashiyama, and Hiraku Onishi
Chem. Pharm. Bull. 33(11), 4662-4670 (1985) (https://www.rhodium.ws/pdf/meth.grignard.oxazolidine.pdf)

Abstract
Chiral N-methyl-4-phenyl-1,3-oxazolidines (2a-e) having a methyl, ethyl, benzyl, isopropyl, and cyclohexyl group at the 2-position of the 1,3-oxazolidine ring were synthesized. Reactions of 2a-e with Grignard reagents gave (1R,1'R)- and (1S,1'R)-1-alkyl- and 1-cycloalkyl-N-2'-hydroxy-1'-phenylethyl-2-phenylethylamines (3a, 3b, 3d, 3e). The absolute configurations of (1R,1'R)-3a and -3e were determined. (R)-1-Methyl- and (R)-1-cyclohexyl-2-phenylethylamines (4a, 4e) were obtained in high yield by hydrogenolysis of (1R,1'R)-3a and -3e.

All in all, this reaction may look very complicated, but it really isn't anything else than the procedure in Post 202649 (Rhodium: "Meth via grignard rxn (Gazz Chim Italiana)", Novel Discourse) with the difference being that the aldehyde has been made into an oxazolidine by reaction with a cheap chiral aminoalcohol. The good thing about using this oxazolidine is that 1) The yields are much higher and 2) the result isn't racemic meth, but a single enantiomer. In the article they make l-methamphetamine, but by choosing the other aminoalcohol enantiomer, the reaction will instead produce d-methamphetamine.

How do you think this reaction could be streamlined? There is really just a single obstacle in this procedure, and that is the removal of the protection group in the final step, for which they use catalytic hydrogenation. What other aminoalcohols could be used, which would be easier to remove?

Could something else be used (which would be a breeze to remove afterwards) if one would be satisfied with racemic product?

^{The Hive - Clandestine Chemists Without Borders}

Rhodium
(Chief Bee)
09-27-04 19:58
No 533428
User Picture       Cathinone from L-PAC
(Rated as: good read)

Here follows another article on the same topic as the one above (grignard addition to oxazolidines):

Untersuchungen zum Konstellationsproblem in der Ephedrinreihe
Hermann Pfanz & Gerhard Kirchner
Ann. Chem. 614, 149-158 (1958) (https://www.rhodium.ws/pdf/ephedrine.oxazolidines.pdf)

The article series below is written by the same author, and contains quite some interesting chemistry:

Imidazoline Δ³ I
Gerhard Kirchner
Ann. Chem. 625, 98-103 (1959) (https://www.rhodium.ws/pdf/ephedrine.imidazoline-1.pdf)
____ ___ __ _

Imidazoline Δ³ II
Gerhard Kirchner
Ann. Chem. 625, 104-107 (1959) (https://www.rhodium.ws/pdf/ephedrine.imidazoline-2.pdf)
____ ___ __ _

Imidazoline Δ³ III
^{Über intramolekulare Oxydoreduktionen}
Gerhard Kirchner
Ann. Chem. 628, 92-95 (1959) (https://www.rhodium.ws/pdf/ephedrine.imidazoline-3.pdf)

The last article contains a synthesis of cathinone from L-PAC by a simple reaction with ammonia and catalytic cyclohexanone:

α-Aminopropiophenone (Norephedrone/Cathinone)

(-)-Phenylacetylcarbinol [L-PAC] (15 g), cyclohexanone (9.8g)), and 15 mL conc. NH4OH was stirred 5 h, the mixture extracted with ether, the extract dried and distilled to give 10-11g of 3-methyl-2-phenyl-1-oxa-4-aza-spiro[4.5]decane (a.k.a (-)-4-methyl-2,2-pentamethylene-5-phenyl-Δ³-oxazoline, I), bp 120°C/0.3 mmHg, n_D²⁰ 1.5370, [α]_D²⁰ -192.7° (96% EtOH).

I (5 g) was heated under reflux for 15 min with anhydrous IPA saturated with HCl, 0.3 ml water was added, and heating continued to give 3.7 g Cathinone·HCl, mp 182°C.

The intermediate heterocycle - 3-methyl-2-phenyl-1-oxa-4-aza-spiro[4.5]decane - can also be made from phenylpropanolamine and cyclohexanone by stirring a THF solution of the reactants over 4A Mol sieves for 24h. Ref: Prasad, K. R. K.; Joshi, N. N.; Indian J.Chem.Sect.B 42(1), 150-153 (2003)

^{The Hive - Clandestine Chemists Without Borders}

Rhodium
(Chief Bee)
10-22-04 23:19
No 537215
User Picture       (-)-phenylglycinol -> d-Methamphetamine
(Rated as: excellent)

The "one-pot" reaction of (-)-phenylglycinol with formaldehyde in the presence of KCN gave the chiral 1,3-oxazolidine (R)-1 as an oil in 94% yield. This synthon was then alkylated twice in the α-position of the cyano group using LDA/MeI followed by LDA/PhCH₂Br, the first substitution giving a product with 38% d.e.^* and the second >66%.

Reduction of the crude product 3 effected decyanation and ring-opening of the oxazolidine to give 4, which in essence is an N-alkylated methamphetamine molecule. If an enantiomerically pure end product is desired, a diastereomer separation is now performed to remove the 15% or so of (R,R)-4 from the remaining 85% of (R,S)-4 through flash chromatography (silica gel, eluting with 5% MeOH in DCM). The unwanted N-alkyl group is then finally removed through overnight hydrogenolysis at atmospherical pressure (MeOH, 10% Pd/C, 12h) to give (S)-N-methyl-α-methyl-phenethylamine 5 (d-Methamphetamine) in 90% yield, with preserved chirality.

The overall yield of d-Methamphetamine from the starting R-(-)-phenylglycinol is thus ~20%.

*d.e. = Diastereomeric Excess - A measure of diastereomer ratio, defined similarly to enantiomeric excess. (http://www.wiu.edu/users/mftkv/Chem331/enantiomericexcess.html)

_{Asymmetric Synthesis IV.}
Preparation of Chiral α-Aminonitriles from a new N-Cyanomethyl-1,3-Oxazolidine Synthon
José L. Marco, Jacques Royer and Henri-Philippe Husson
Tetrahedron Letters 26(30), 3567-3570 (1985) (https://www.rhodium.ws/pdf/cyanomethyl-4-phenyl-13-oxazolidine.pdf)

Abstract: The synthesis of (-)-N-cyanomethyl-4-phenyl-1,3-oxazolidine 1 is reported. Good yields and moderate diastereomeric excesses of mono- and di-substituted α-aminonitriles were obtained from this simple chiral template.

Preparation of (-)-N-cyanomethyl-4-phenyl-1,3-oxazolidine 1

To a stirred solution of (-)-phenylglycinol (23.62g, 0.16 mol), KCN (10.4g, 0.16 mol) in water (650 mL) at pH ~3 (citric acid) was added over 30 min at room temp a solution of formaldehyde (40%, 260 mL). The reaction mixture was stirred for ar additionnal 30 min, then basified (Na₂CO₃) and extracted (CH₂Cl₂). The combined organic fractions were washed with water, dried (Na₂SO₄) and concentrated to give a yellow oil which was purified by flash chromatography (SiO₂, hexane-AcOEt, 80:20). 1 was obtained as a colorless oil (31.15g, 94% yield, [α]²⁰_D -173°(CHCl₃, c=1.4)).

Alkylation of 1 with Methyl Iodide

To a stirred solution of LDA/HMPA (1:1, 1.1 eq. 0.48 M in THF) at -78°C, was added 1 (1 eq., 0.66M in THF) via syringe over 5 min; after 15 min 1.1 eq. of MeI was added. The reaction mixture was stirred for 1 h, quenched by NH₄Cl then extracted with ether, dried and concentrated to dryness. Flash chromatography of the residual oil (SiO₂, hexane-EtOAc, 85:15) separated the isomers to give 2 as the major product, yield 55% (38% d.e.) [α]²⁰_D -282° (c=2.4, CDCl₃)

_{Asymmetric Synthesis IX:}
Preparation of Chiral α-Substituted Phenethylamines
J.L. Marco, J. Royer & H.-P. Husson
Synth. Commun. 17(6), 669-676 (1987) (https://www.rhodium.ws/chemistry/meth.n-cyanomethyloxazolidine.html)

Abstract: (S)-N-methyl-α-methyl-phenethylamines 5a-d were obtained in 56-62% e.e. from the chiral synthon (-)-N-cyanomethyl-4-phenyl-1,3-oxazolidine-1.

Alkylation of 2 with Benzyl Bromide
To a stirred solution of LDA/HMPA (1:1; 5 mmol, prepared from 3.12 mL of BuLi 1.6 M and 0.75 mL of diisopropylamine at -10°C/-30°C under a nitrogen atmosphere) in THF (20 mL) was added 2 (0.909g, 4.5 mmol, THF, -78°C) via syringe over 5 min. After 20 min, the resultant anion solution was added benzyl bromide (2 equiv.) and the mixture was stirred at -78°C for 1 h, quenched by NH₄Cl then extracted with ether dried and concentrated to dryness. Flash chromatography of the residual oil (SiO₂, hexane-AcOEt, 80:20) yielded compound 3, which was used in the next step without further purification.

Reductive Decyanation/Ring-Opening of 3
NaBH₄ (1.1 eq.) was added portionwise to a solution of 3 in EtOH (~0.4 M); stirring was continued at room temp overnight. The solvent was removed and the residue taken up in DCM, washed with H₂O and brine, dried over Na₂SO₄ and evaporated to dryness. The oily residue was purified by flash-chromatography (DCM-MeOH, 95:5) to give 4. The diastereomeric excess of the RS isomer was 66% and the overall yield from 1 was 30%.

Hydrogenolysis of 4 to give (S)-5 (d-Methamphetamine)
A methanolic solution (~0.2 M) of 4 was hydrogenolysed overnight at room temp, using 1 atm. H₂ in the presence of 10% Pd/C. The reaction mixture was then filtered through a celite bed and the filtrate evaporated in vacuo to yield an oily residue which was purified by flash chromatography on silica (DCM-MeOH) to give (S)-5 (d-Methamphetamine) in 90% yield (66% e.e.).

^{The Hive - Clandestine Chemists Without Borders}

	https://the-hive.archive.erowid.org	the-hive@erowid.org



Powdered by Gerbal Wheels(TM) 1.10, 2015, DEA-Soft Enterprises. All rights reserved.
Links Erowid Rhodium

	All 3 posts		Subject: Grignard Synthesis of Chiral Amphetamines		Please login to post		Down


		Rhodium (Chief Bee) 05-31-04 17:15 No 510550				Grignard Synthesis of Chiral Amphetamines (Rated as: good read)
						_{Asymmetric α-Substituted Phenethylamines. V.} Synthesis of Chiral 1-Alkyl-2-phenylethylamines via Grignard Reaction of 4-Phenyl-1,3-oxazolidines Hiroshi Takahashi,Yasuhiro Chida, Kimio Higashiyama, and Hiraku Onishi Chem. Pharm. Bull. 33(11), 4662-4670 (1985) (https://www.rhodium.ws/pdf/meth.grignard.oxazolidine.pdf) Abstract Chiral N-methyl-4-phenyl-1,3-oxazolidines (2a-e) having a methyl, ethyl, benzyl, isopropyl, and cyclohexyl group at the 2-position of the 1,3-oxazolidine ring were synthesized. Reactions of 2a-e with Grignard reagents gave (1R,1'R)- and (1S,1'R)-1-alkyl- and 1-cycloalkyl-N-2'-hydroxy-1'-phenylethyl-2-phenylethylamines (3a, 3b, 3d, 3e). The absolute configurations of (1R,1'R)-3a and -3e were determined. (R)-1-Methyl- and (R)-1-cyclohexyl-2-phenylethylamines (4a, 4e) were obtained in high yield by hydrogenolysis of (1R,1'R)-3a and -3e. All in all, this reaction may look very complicated, but it really isn't anything else than the procedure in Post 202649 (Rhodium: "Meth via grignard rxn (Gazz Chim Italiana)", Novel Discourse) with the difference being that the aldehyde has been made into an oxazolidine by reaction with a cheap chiral aminoalcohol. The good thing about using this oxazolidine is that 1) The yields are much higher and 2) the result isn't racemic meth, but a single enantiomer. In the article they make l-methamphetamine, but by choosing the other aminoalcohol enantiomer, the reaction will instead produce d-methamphetamine. How do you think this reaction could be streamlined? There is really just a single obstacle in this procedure, and that is the removal of the protection group in the final step, for which they use catalytic hydrogenation. What other aminoalcohols could be used, which would be easier to remove? Could something else be used (which would be a breeze to remove afterwards) if one would be satisfied with racemic product? ^{The Hive - Clandestine Chemists Without Borders}



		Rhodium (Chief Bee) 09-27-04 19:58 No 533428				Cathinone from L-PAC (Rated as: good read)
						Here follows another article on the same topic as the one above (grignard addition to oxazolidines): Untersuchungen zum Konstellationsproblem in der Ephedrinreihe Hermann Pfanz & Gerhard Kirchner Ann. Chem. 614, 149-158 (1958) (https://www.rhodium.ws/pdf/ephedrine.oxazolidines.pdf) The article series below is written by the same author, and contains quite some interesting chemistry: Imidazoline Δ³ I Gerhard Kirchner Ann. Chem. 625, 98-103 (1959) (https://www.rhodium.ws/pdf/ephedrine.imidazoline-1.pdf) ____ ___ __ _ Imidazoline Δ³ II Gerhard Kirchner Ann. Chem. 625, 104-107 (1959) (https://www.rhodium.ws/pdf/ephedrine.imidazoline-2.pdf) ____ ___ __ _ Imidazoline Δ³ III ^{Über intramolekulare Oxydoreduktionen} Gerhard Kirchner Ann. Chem. 628, 92-95 (1959) (https://www.rhodium.ws/pdf/ephedrine.imidazoline-3.pdf) The last article contains a synthesis of cathinone from L-PAC by a simple reaction with ammonia and catalytic cyclohexanone: α-Aminopropiophenone (Norephedrone/Cathinone) (-)-Phenylacetylcarbinol [L-PAC] (15 g), cyclohexanone (9.8g)), and 15 mL conc. NH4OH was stirred 5 h, the mixture extracted with ether, the extract dried and distilled to give 10-11g of 3-methyl-2-phenyl-1-oxa-4-aza-spiro[4.5]decane (a.k.a (-)-4-methyl-2,2-pentamethylene-5-phenyl-Δ³-oxazoline, I), bp 120°C/0.3 mmHg, n_D²⁰ 1.5370, [α]_D²⁰ -192.7° (96% EtOH). I (5 g) was heated under reflux for 15 min with anhydrous IPA saturated with HCl, 0.3 ml water was added, and heating continued to give 3.7 g Cathinone·HCl, mp 182°C. The intermediate heterocycle - 3-methyl-2-phenyl-1-oxa-4-aza-spiro[4.5]decane - can also be made from phenylpropanolamine and cyclohexanone by stirring a THF solution of the reactants over 4A Mol sieves for 24h. Ref: Prasad, K. R. K.; Joshi, N. N.; Indian J.Chem.Sect.B 42(1), 150-153 (2003) ^{The Hive - Clandestine Chemists Without Borders}



		Rhodium (Chief Bee) 10-22-04 23:19 No 537215				(-)-phenylglycinol -> d-Methamphetamine (Rated as: excellent)
						The "one-pot" reaction of (-)-phenylglycinol with formaldehyde in the presence of KCN gave the chiral 1,3-oxazolidine (R)-1 as an oil in 94% yield. This synthon was then alkylated twice in the α-position of the cyano group using LDA/MeI followed by LDA/PhCH₂Br, the first substitution giving a product with 38% d.e.^* and the second >66%. Reduction of the crude product 3 effected decyanation and ring-opening of the oxazolidine to give 4, which in essence is an N-alkylated methamphetamine molecule. If an enantiomerically pure end product is desired, a diastereomer separation is now performed to remove the 15% or so of (R,R)-4 from the remaining 85% of (R,S)-4 through flash chromatography (silica gel, eluting with 5% MeOH in DCM). The unwanted N-alkyl group is then finally removed through overnight hydrogenolysis at atmospherical pressure (MeOH, 10% Pd/C, 12h) to give (S)-N-methyl-α-methyl-phenethylamine 5 (d-Methamphetamine) in 90% yield, with preserved chirality. The overall yield of d-Methamphetamine from the starting R-(-)-phenylglycinol is thus ~20%. d.e. = Diastereomeric Excess - A measure of diastereomer ratio, defined similarly to enantiomeric excess. (http://www.wiu.edu/users/mftkv/Chem331/enantiomericexcess.html) _{Asymmetric Synthesis IV.} Preparation of Chiral α-Aminonitriles from a new N-Cyanomethyl-1,3-Oxazolidine Synthon José L. Marco, Jacques Royer and Henri-Philippe Husson* Tetrahedron Letters 26(30), 3567-3570 (1985) (https://www.rhodium.ws/pdf/cyanomethyl-4-phenyl-13-oxazolidine.pdf) Abstract: The synthesis of (-)-N-cyanomethyl-4-phenyl-1,3-oxazolidine 1 is reported. Good yields and moderate diastereomeric excesses of mono- and di-substituted α-aminonitriles were obtained from this simple chiral template. Preparation of (-)-N-cyanomethyl-4-phenyl-1,3-oxazolidine 1 To a stirred solution of (-)-phenylglycinol (23.62g, 0.16 mol), KCN (10.4g, 0.16 mol) in water (650 mL) at pH ~3 (citric acid) was added over 30 min at room temp a solution of formaldehyde (40%, 260 mL). The reaction mixture was stirred for ar additionnal 30 min, then basified (Na₂CO₃) and extracted (CH₂Cl₂). The combined organic fractions were washed with water, dried (Na₂SO₄) and concentrated to give a yellow oil which was purified by flash chromatography (SiO₂, hexane-AcOEt, 80:20). 1 was obtained as a colorless oil (31.15g, 94% yield, [α]²⁰_D -173°(CHCl₃, c=1.4)). Alkylation of 1 with Methyl Iodide To a stirred solution of LDA/HMPA (1:1, 1.1 eq. 0.48 M in THF) at -78°C, was added 1 (1 eq., 0.66M in THF) via syringe over 5 min; after 15 min 1.1 eq. of MeI was added. The reaction mixture was stirred for 1 h, quenched by NH₄Cl then extracted with ether, dried and concentrated to dryness. Flash chromatography of the residual oil (SiO₂, hexane-EtOAc, 85:15) separated the isomers to give 2 as the major product, yield 55% (38% d.e.) [α]²⁰_D -282° (c=2.4, CDCl₃) _{Asymmetric Synthesis IX:} Preparation of Chiral α-Substituted Phenethylamines J.L. Marco, J. Royer & H.-P. Husson Synth. Commun. 17(6), 669-676 (1987) (https://www.rhodium.ws/chemistry/meth.n-cyanomethyloxazolidine.html) Abstract: (S)-N-methyl-α-methyl-phenethylamines 5a-d were obtained in 56-62% e.e. from the chiral synthon (-)-N-cyanomethyl-4-phenyl-1,3-oxazolidine-1. Alkylation of 2 with Benzyl Bromide To a stirred solution of LDA/HMPA (1:1; 5 mmol, prepared from 3.12 mL of BuLi 1.6 M and 0.75 mL of diisopropylamine at -10°C/-30°C under a nitrogen atmosphere) in THF (20 mL) was added 2 (0.909g, 4.5 mmol, THF, -78°C) via syringe over 5 min. After 20 min, the resultant anion solution was added benzyl bromide (2 equiv.) and the mixture was stirred at -78°C for 1 h, quenched by NH₄Cl then extracted with ether dried and concentrated to dryness. Flash chromatography of the residual oil (SiO₂, hexane-AcOEt, 80:20) yielded compound 3, which was used in the next step without further purification. Reductive Decyanation/Ring-Opening of 3 NaBH₄ (1.1 eq.) was added portionwise to a solution of 3 in EtOH (~0.4 M); stirring was continued at room temp overnight. The solvent was removed and the residue taken up in DCM, washed with H₂O and brine, dried over Na₂SO₄ and evaporated to dryness. The oily residue was purified by flash-chromatography (DCM-MeOH, 95:5) to give 4. The diastereomeric excess of the RS isomer was 66% and the overall yield from 1 was 30%. Hydrogenolysis of 4 to give (S)-5 (d-Methamphetamine) A methanolic solution (~0.2 M) of 4 was hydrogenolysed overnight at room temp, using 1 atm. H₂ in the presence of 10% Pd/C. The reaction mixture was then filtered through a celite bed and the filtrate evaporated in vacuo to yield an oily residue which was purified by flash chromatography on silica (DCM-MeOH) to give (S)-5 (d-Methamphetamine) in 90% yield (66% e.e.). ^{The Hive - Clandestine Chemists Without Borders}

All 3 posts	End of thread	Top