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Reducing amides to amines

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java:
As I searched some of the old threads  where I found a posting by Post 348699 (Cyrax: "Li/Na Borohydride and Trimethylchlorosilane", Serious Chemistry) where he quotes a text from Rhodium....

Lithium/Sodium Borohydride and Trimethylchlorosilane - An Unusually Strong and Versatile Reducing Agent
Angew. Chem. Int. Ed. Engl. Vol 28, No. 2, 218-220 (1989) (https://www.thevespiary.org/rhodium/Rhodium/chemistry/nabh4-tmscl.html)

where they use procedure A on example 7, where the amide is reduced to an amine , hence  the procedure will work for the reduction of the acylated amine in phenylalanine once the COOH is reduced ,....java

lugh:
I've read the methods suggested by Lego and others in converting the amide to easier leaving groups, thioamides, that can be removed easily but need ....

The Preparation and Chemical Properties of Thionamides.
Richard N. Hurd, George DeLaMater;
Chem. Rev.61(1); 45-86,1961
--- End quote ---


Chem. Rev.61(1); 45-86,1961



8)

Rhodium:
Zinc Borohydride: Reduction of Amides to Amines
S. Narasimhan, S. Madhavan, R. Balakumar & S. Swarnalakshmi
Synth. Commun. 27(3), 391–394 (1997) (https://www.thevespiary.org/rhodium/Rhodium/chemistry/amide2amine.zn-borohydride.html)

Abstract
Zinc borohydride reduces secondary amides to the corresponding N-ethyl amines in excellent yields.
The reduction requires only stoichiometric quantities of hydride and does not require the addition of any Lewis acid.
The amides are isolated by simple hydrolysis of the reaction mixture.

Lego:
An efficient sequence for the preparation of small secondary amine hydrochloride salts for focused library generation without need for distillation or chromatographic purification
Gene M. Dubowchik, Jodi A. Michne and Dmitry Zuev
Bioorg. Med. Chem. Lett., 2004, 14 , 3147-3149
DOI:10.1016/j.bmcl.2004.04.014


Abstract: Collections of small secondary amines for compound library generation can be efficiently prepared by amide reduction using BH3–THF or Red-Al followed by brief methanolysis, trapping with di-tert-butyl dicarbonate, and deprotection with 4M HCl in dioxane. The sequence requires no chromatography or distillation and provides multi-gram quantities of pure HCl salts in a short time.



Reagents and conditions:
(a) R2NH2, Et3N, CH2Cl2, 0°C to rt
(b) (i) BH3–THF (3 equiv), reflux, 14 h;(ii) MeOH, reflux, 2 h; (iii) Boc2O (1.4 equiv), CH2Cl2, rt, 14 h
(c) 4M HCl/dioxane (1.2 equiv), CH2Cl2, rt, 14 h.

Representative synthetic procedure for 4c:
A stirred solution of 3,3,3-trifluoroacetic acid N-hydroxysuccinimide ester (12.98 g, 57.65 mmol) in CH2Cl2 (80 mL) at 0 °C was treated with cyclopropylmethylamine (5.0 mL, 1 equiv). The mixture was stirred at rt for 14 h and then concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with water, brine, dried over MgSO4, and evaporated to give the crude amide. This was dried under high vacuum for several hours and then, under nitrogen at 0 °C, it was carefully treated with 1M BH3 in THF (173 mL, 3 equiv). The mixture was heated at reflux for 14 h and then re-cooled to 0 C. MeOH (50 mL) was added carefully to avoid excess foaming, and the mixture was heated at reflux for 5 h. Upon re-cooling to 0 C, a solution of Boc2O (17.62 g, 1.4 equiv) in CH2Cl2 (25 mL) was added. The resulting mixture was stirred at rt overnight and then concentrated in vacuo. The residue was partitioned between ethyl acetate and water.
The organic was washed with water, brine, dried over MgSO4, and evaporated to give the crude Boc-protected amine. This was dissolved in CH2Cl2 (25 mL) and treated with 4M HCl in dioxane (17 mL, 1.2 equiv), carefully to avoid uncontrolled bubbling. The mixture was stirred at RT overnight and then evaporated. The resulting white solid was triturated with ether and the product was collected by filtration, washed with ether, and dried in vacuo (10.10 g, 86%).

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