Author Topic: Lithium and amine dissolving metal reduction  (Read 4021 times)

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Lithium and amine dissolving metal reduction
« on: March 19, 2004, 05:56:00 PM »
Abstract of

Patent US5675038

The invention is directed to a process for reducing or reductively cleaving an organic compound susceptible to dissolving metal reduction comprising exposing the organic compound to a solution of lithium in a polyamine including at least two amino groups, selected from the group consisting of primary and secondary amino groups and mixtures thereof, e.g. ethylenediamine and R-NH2, optionally containing a lower alkyl alcohol, wherein R is chosen from the group consisting of ethyl, propyl, and butyl, including all straight and branched chain isomers thereof, for a time sufficient to effect reduction.


Preliminary experiments with lithium in lower alkyl amines alone, such as in n-propylamine or isopropylamine made clear that reduction is very slow and subsequently the yields are not as high. Essentially the reaction does not proceed without the addition of a polyamine, such as ethylenediamine, to the reaction mixture. The addition results in reaction times that are faster than comparable reductions done under Birch conditions or lithium in amine (Benkeser) conditions. At least one mole of polyamine, e.g. ethylenediamine, per gram atom of lithium is used in reactions utilizing the processes of the present invention, optionally more than one equivalent may be added. The present invention may be carried out without any hydroxylic Solvent, but in some reactions, an added hydroxylic solvent, such as t-butanol, may be beneficial to the yield of a desired product or isomer of a product. Addition of an alcohol provides a source of protons more acidic than the amine groups present in the reaction solution. This can assist in protonation of intermediates or products in the reaction and so speed the reaction, reduce formation of unwanted by-products or isomers, or allow the reduction to proceed beyond that which would occur without protonation of an intermediate. One skilled in the art can determine when such addition is beneficial, either through the analysis of the predicted reaction mechanism or through experimentation.

The following examples are mechanistically very similar to the reduction of pseudoephedrine, and should be studied in more detail:


Reduction of anisole. Lithium, in small pieces, (8.75 g, 1.25 gram-atoms) was added to a solution of anisole (54 g, 0.5 mol) in n-propylamine (400 mL), ethylenediamine (105 g (1.75 mol) and t-butanol (111 g, 1.5 mol) cooled to -18 DEG . The temperature increased to 12 DEG and then decreased to -5 DEG . After 2 hr all of the lithium had reacted and the reaction mixture was diluted with 800 mL of water added slowly. The mixture was extracted with ether (3.times.250 mL). The ether extracts were washed with water (3.times.200 mL) and brine (1.times.100 mL) and evaporated. The residue was distilled to give 27.5 g (50% of 1-methoxy-1,4-cyclohexadiene containing 10% of 1-methoxy-1,3-cyclohexadiene by glpc and nmr.


Reduction of naphthalene. Lithium (3.5 g, 0.5 gram-atom), in small pieces, was added in one portion to a solution, cooled to -16 DEG , of naphthalene (12.8 g, 0.10 mol) in n-propylamine (100 mL), ethylenediamine (30 g, 0.5 mol) and t-butanol (44.4 g, 0.6 mol). The solution warmed to 45 DEG and cooled to 0 DEG in 15 min. After 15 min, the reaction mixture was poured over 150 g of ice and 100 mL of water and then extracted with ether (3.times.150 mL). The ether was washed with water (2.times.100 mL) and brine (1.times.100 mL). The ether was evaporated under reduced pressure to give 12.2 g of a colorless solid which was triturated with methanol, filtered and dried to give crude 1,4,5,8-tetrahydronaphthalene which was crystallized from methanol (25 mL) to give 8.6 g (65%) of 1,4,5,8-tetrahydronaphthalene which was 93% pure by glpc.


  • Guest
Nice! Well now I know!
« Reply #1 on: March 20, 2004, 07:17:00 AM »
Rhodium nice find!

The fact that it is slower than the NH3 might not be overly bad since the NH3 is so fast.

Title: Isopropylamine . CAS Registry number: [75-31- CAS name(s): 2-Propanamine Additional name(s): 2-aminopro Molecular formula: C 3 H 9 N Molecular weight: Percent Composition: C 60.96%, H 15.35%, N Line Formula: (CH 3 ) 2 CHNH 2 Literature references: Prepn from acetone + NH 3 : Skita, Keil, Ber. 61, 1682 (1928); Norton et al., J. Org. Chem. 19, 1054 (1954); from acetone oxime: Winans, Ad kins, J. Am. Chem. Soc. 55, 2056 (1933). Toxicity study: H. F. Smyth et al., Arch. Ind. Hyg. Occup. Med. 4, 119 (1951). Properties:  Colorless, flammable liquid; ammonia odor; strong base. d 4 15 0.694 . mp minus101degrees . bp 33-34degrees . n D 15 1.3770 . Flash pt, open cup: minus15degreesF (minus26degreesC). Miscible with water, alcohol, ether. LD 50 orally in rats: 820 mg/kg (Smyth) . Density: d 4 15 Boiling point: bp 33-34 Melting Point: minus101 Refraction index: n D 15 1.3770


  • Guest
Lithium in Ethylenediamine, Birch-Benkeser etc.
« Reply #2 on: September 20, 2004, 02:42:00 AM »
Lithium in Ethylenediamine: A New Reducing System for Organic Compounds
L. Reggel, R.A. Friedel, I. Wender

J. Org. Chem. 22, 891-894 (1957)


A new metal-amine reducing system, lithium in ethylenediamine, is described. It reduces aromatic rings to monoolefins and to cycloparaffins; reduces phenols; cleaves ethers; reduces ketones to alcohols; and reduces acetylenes and both terminal and internal olefins to alkanes. It appears to be the most powerful, and perhaps the least selective, of the metal-amine systems.
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Reduction of Organic Compounds by Lithium in Low Molecular Weight Amines. VII.
The Preparation of Dihydroaromatics. A Comparison of the Lithium-Amine and Birch Reduction Systems

Robert A. Benkeser, Merwyn L. Burrous, James J. Hazdra, Edwin M. Kaiser

J. Org. Chem. 28, 1094-1097 (1963)


Four different aromatic compounds are reduced by lithium-methylamine-alcohol combinations as well as by sodium-ammonia-alcohol (Birch reduction). In each case unconjugated dienes (dihydroaromatics) are formed in comparable yields. Unlike the Birch method, wherein an excess of metal may be employed, it is shown that an excess of metal in the amine-alcohol system results in the formation of considerable amounts of monoolefins rather than dihydro products. Apparently the alcohol cannot prevent isomerization of the unconjugated dihydro products to conjugated dienes entirely under these circumstances. It is shown that at least two equivalents of water (based on aromatic) can be tolerated in the lithium-amine reduction of cumene. The reduction of both the aromatic and its diene intermediates is so rapid in this system that these organic materials compete successfully for electrons with the hydrogen of the water molecules.
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A Comparison of Methods Using Lithium/Amine and Birch Reduction Systems
Edwin M. Kaiser

Synthesis 391-415 (1972)


Treatment of unsaturated organic compounds with sodium and alcohols in ammonia (the Birch reduction) or with lithium in low molecular weight amines (the Benkeser reduction) generally affords partially or fully reduced products, respectively, though reductive cleavages sometimes also occur. This review discusses the similarities and differences between the Birch and Benkeser methods as illustrated by their application to aromatics, heteroaromatics, alkynes, alkenes, ethers, alcohols, amines, carboxylic acids, ketones, heterocycles, and other compounds. In general, the Benkeser reduction is more powerful but less selective than the Birch reduction; however, the selectivity of the former method is increased by a judicious choice of solvents.
____ ___ __ _

Also see:

Post 375819 (missing)

(koretexx: "Birch/Benkeser solvents,co-solvents,catalysts etc.", Stimulants)

Post 288097 (missing)

(PrimoPyro: "Birch-Like Reduction With Ethylamine", Stimulants)


  • Guest
Birch (over)reduction of (-)-Ephedrine
« Reply #3 on: September 22, 2004, 06:06:00 PM »
I thought this article would be good for the identification of 1-(1,4-cyclohexadien-1-yl)-N-methyl-2-propanamine (2) which is the product resulting from "overreduction" of (pseudo)ephedrine under Birch conditions.

Birch Reduction of (-)-Ephedrine.
Formation of a New, Versatile Intermediate for Organic Synthesis

Gury Zvilichovsky and Isra Gbara-Haj-Yahia, J. Org. Chem., 69, 5490-5493 (2004)

The reduction of (-)-ephedrine by lithium in liquid ammonia resulted in the formation of (S)-1-(1,4-cyclohexadien-1-yl)-N-methyl-2-propanamine. In addition to the reduction of the aromatic ring, the hydroxy group was reduced as well. The resulting 1,4-cyclohexadienyl group is a potentially versatile intermediate for further synthetic transformations. The restriction to rotation of the C-N bond in N-benzoyl-1-(1,4-cyclohexadien-1-yl)-N-methyl-2-propanamine is described.


Birch Reduction of (-)-Ephedrine

(-)-Ephedrine (6 g, 0.036 mol) was placed in a 1 L flask on a dry ice-acetone bath with a dry ice condenser. Liquid ammonia (300 mL) was introduced, and then tert-butyl alcohol (100 mL) was added slowly during 1 h. Small pieces of lithium ribbon (3 g, 0.4 mol) were added during 6 h with stirring, retaining the blue color of the solution. The reaction mixture was stirred and allowed to warm to room temperature in the hood overnight, while most of the ammonia evaporated. Solvents were removed by vacuum, and the white residue was dissolved in water (150 mL). The resulting 1-(1,4-cyclohexadien-1-yl)-N-methyl-2-propanamine (2) was extracted by ethyl acetate (oil, 4 g, 73%).

For elemental analysis, a small portion was transformed into the HCl salt:
The oil (0.05 g) was dissolved in dichloromethane (1 mL). Ethanolic HCl (4 N, 0.5 mL) and excess ether were added. The salt precipitated and was collected by filtration (0.05g, mp 185°C).


  • Guest
no doubt good read!
« Reply #4 on: September 24, 2004, 10:02:00 AM »
So like...I may be behind, on all the birch mechanics and all, but they dont even use any lye or an A/B to finish when birching do they?


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« Reply #5 on: September 24, 2004, 06:43:00 PM »