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Reducing amides to amines

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java:
To follow up on the catalytic hydrogenation conversation  using Pd/charcoal to reduce amides to amines....

.".... sorry for the delay, I had been out of station for office work and so could not go to library to check these old references. Now I have gone thru them, and feel that you try using Platinum or better Palladium catalyst on charcoal support, the details will be available on Johnson-Matthey site or any other noble metal catalyst manufacturers. Normal procedure will be to use suitable solvent like methanol/ethanol/isoprpyl alcohol and about 0.5 gms of catalyst ( loading 5%) per gm.mole of starting amide and follow temperature/pressure profile at which you get exotherm. Limit pressures to 3-4 kg/cm2g as you desire and increase temperature to max. 100 degrees centigrade."

I was not given any references  to quote but only the comments from a hands on researcher ......I hope this sheds some light, on the catalytic hydrogenation of amides >>>amines  at low pressure

slappy:
You cannot reduce amides with Palladium on Carbon under any normal conditions. Maybe 0.00001% would end up reduced, but that's it. I have taken amides and polyamides from 40psi-500psi with copious amounts of fresh 10% Pd/C and never had any reduction. With PtO2 in acid I would beliveve that that could that happen though.

Besides you need to have an acidic enviroment to dehydate the hemiaminal formed.  -C(=O)N- -> -CH(OH)N- -(-H2O)-> -CH=N+- -> -CH2-NH-. When you reduce with a borohydride or LAH, you have borane or alane present which are lewis acids.

Lego:
Lego's idea is as follows:

1) Convert the amide to a thioamide with any known reagent. Lego would suggest P4S10 or Lawesson's reagent (p-MeOC6H4)2P2S4). The first is cheap and yields are OK, the second is a bit more expensive but yields are usually better.

Just a few interesting examples:
Organic Letters, 1999, 1(5), 697-700
DOI:10.1021/ol990629a

Microwave-Accelerated Solvent-Free Synthesis of Thioketones, Thiolactones, Thioamides, Thionoesters, and Thioflavonoids

An expeditious, solvent-free, and high yield conversion of ketones, flavones, isoflavones, lactones, amides, and esters to the corresponding thio analogues is described utilizing Lawesson's reagent in a process that circumvents the use of dry solvents and excess of the reagent.



Synthetic Communications, 1990, 20(19), 3085-3095
In situ reagents for thionation of amides, peptides and lactams

An agent, prepd. from 1:1 P2S5 and Na2CO3 in situ, is used for thionation of amides, amino acids, peptides, and lactams.  Yields range from 28 to 96%.



The latest article on this topic (especially check the reference mentioned in the beginning):
J. Org. Chem., 2003, 68(14), 5792-5794
DOI:10.1021/jo0344485
Mild Method for the Conversion of Amides to Thioamides

Aqueous ammonium sulfide was found to be an ideal substitute for hydrogen sulfide for the thiolysis of activated amides. High yields of the corresponding thioamides were obtained for a broad range of substrates, using two different procedures that are both operationally simple and inexpensive, as well as amenable to large-scale preparation. Preliminary results indicate that aqueous ammonium sulfide may also replace hydrogen sulfide in the synthesis of thionoesters from amides.



There are so many more articles concerning this topic, but this is enough to give you an idea of how this versatile this reaction is.



2) Reduction of the thioamide to an amine.
As Al/Hg is a common reducing agent in clandestine chemistry here is a reference:

Ber., 1921, 54B, 1080-1081
Thioamides. II. Reduction of thioamides to primary amides.  

By the use of Al-Hg in a neutral medium thioamides can be reduced to the corresponding primary amines with good yields.  Thus, 0.1 mol. PhCSNH2 in 4 parts 99% alc. and 13 g. Al-Hg slowly treated under a reflux with turbining with 13 cc. H2O, heated 3 hrs. at 60-70°, made alk. with NaOH, distd. with steam, acidified with HCl, concd., decompd. with concd. KOH, taken up with Et2O and dried with K2CO3 give PhCH2NH2, b. 184.5°.  MeCSNH2 (1 g.) in 10 cc. of 90% alc. similarly reduced with 1 g. Al-Hg and 1 cc. H2O gives EtNH2.

Or take a look in Chemical Reviews, 1961, 61, 45-86. Electrolysis, catalytic hydrogenation, metal/acid-combinations can also be used to reduce thioamides.


If there is any further interest on this kind of reaction Lego will post explicit experimental details and search this fucking reference where a thioamide was reduced in 90% yield with Zn/HOAc.











Ooops, while looking for the exact references Lego found an article with a similiar, more sophisticated reaction.

Tetrahedron Letters, 1980, 21(42), 4061-4064 
A convenient method for the selective reduction of amides to amines

Amides were selectively reduced to the corresponding amines in high yield via their thioamides and (alkylthio)methyleniminium salts.  E.g., PhCH2CONMe2 on treatment with (p-MeOC6H4)2P2S4 (PhMe, under Ar, 100°, 4 h) gave 90% PhCH2CSNMe2.  The iminium salt obtained by treating the latter with Et3O+ BF4- (CH2Cl2, under Ar, 0°, 5 min, then room temp., 45 min), was reduced quant. with NaBH4 (MeOH, 0°, 5 min, then room temp., 2 h) to Ph(CH2)2NMe2.  This procedure is compatible with isolated and conjugated double bonds, esters, nitro groups, and sulfonamides.

Barium:
Raney nickel is known to easily rip sulfur from organic compounds to form NiS irreversily. Perhaps urushibara nickel, in some form, have the same properties. With Raney nickel it is just a matter of allowing the thio compound to react with a slight excess nickel at a slightly elevated temperature and in a suitable solvent. Voila, a desulfurised compound.

Lego:
Here is the reference for the reduction of a secondary thioamide with Zn/HCl in EtOH (yield: 91%).

http://www.unibas.ch/mdpi/ecsoc-3/a0020/a0020.html

More on this topic will follow when Lego's alter ego will not bee busy during the opening times of the library.


N-METHYLTYRAMINE AND N,O-DIMETHYLTYRAMINE SYNTHESIS VIA INTERMEDIATE 4-METHOXYPHENYL-N-METHYLTHIOACETAMIDE

Vladimir N. Bulavka*, Alexander N. Shchavlinskii and Oleg N. Tolkachev

All-Russian Institute of Medicinal and Aromatic Plants (VILAR);

Grina str., 7, Moscow, 113628, Russian Federation.

*Present address: Scientific-Research Phototechnical Institute on Slavich Company (NIFTI-Slavich);

Mendeleev sq. 2, Pereslavl-Zalesskii, Yaroslavl region, 152140, Russian Federation.

E-mail: nifti@slavich.botik.ru

Received: 30 July 1999 / Uploaded: 13 August 1999

Keywords: galanthamine synthesis half-products, N-methyltyramine, N-methyltyramine ethers, N,O-dimethyltyramine, arylthioacetamide, Willgerodt-Kindler reaction

N-Methyltyramine and its alkyl or benzyl ethers are common intermediate products in the syntheses of narwedine, and galanthamine alkaloids [1-8]. They are usually produced from the corresponding arylacetamides by lithium aluminium hydride reduction. In order to avoid application of inflammable lithium aluminium hydride bulgarian scientists have transformed arylacetamide to arylthioacetamide with phosphorus (V) sulfide with following reduction of arylthioacetamide with complex sodium borohydride - nickel or cobalt chloride agents [7, 8].

Here we present a new short way route to N-methyltyramine and its ethers via the corresponding aryl-N-methylthioacetamides, shown at the scheme 1 at the example of N-methyltyramine and N,O-dimethyltyramine synthesis.

Scheme 1.



--> a: 92%
--> b: 57-58%
--> c: 91%
--> d: 98%
total 46-47% total 48-49%

a) H3CCOBr, AlCl3, ClCH2CH2Cl.
b) H3CNH2.HCl, S8 , H3CCO2Na, (H3C)2NCHO, 115oC, 3h.
c) Zn (dust) and 36% HCl(aq.) in ethanol
d) 36% HCl(aq.), refluxion

Anisole was smoothly acetylated in a classical conditions [9] with acetyl bromide and aluminium chloride in dichloroethane to produce 4-methoxyacetophenone in 92% yield.

Phenylacetic acid thioamides are usually synthesized by the Willgerodt-Kindler reaction from the corresponding substituted acetophenones, amines, and sulfur. We have studied several alternative routes to the 4-methoxyphenyl-N-methylthioacetamide synthesis shown at the scheme 2.

Scheme 2.



a) H3CNH2, S8, 170-180oC, 3h (yield 10,4%, and 21,9% by-product amide).
b) H3CNH2.HCl, S8 , H3CCO2Na, (H3C)2NCHO, 115oC, 3h (yield 58,4%).
c) H3CNH2.HCl, S8, N(C2H5)3, 4-H3CC6H4SO3H.H2O, (H3C)2NCHO, 75oC, 72h (yield 57%)
d) H3CNHCHO, S8, 190oC, 20h (yield 35%).
e) H3CNH2 .HCl, Na2CO3, CaO, N(C2H5)3, -7oC (isolated mixture imine : ketone 77:23 (1H NMR) formed, used for the next stage without separation).
f) S8, N(C2H5)3, (H3C)2NCHO, 70oC (total yield on two stages 21,5%).

The best results were produced according to routes b and c.

The key thioamide was isolated chromatographically on alumina or silica gel.

In classical conditions of the Willgerodt-Kindler reaction in the sealed tube [10] the desired thioamide was obtained in only 10.4% yield, while the corresponding by-product amide was also isolated in 21.9% yield. In order to avoid the application of high pressure, two-stage synthesis was carried out via intermediate 4-methoxyacetophenone methylimine [11] by method [12, 13] in 21.5% total yield.

Earlier proposed method of carrying out the Willgerodt-Kindler reaction with volatile lower secondary amines, e. g. dimethylamine, using its hydrochloride and sodium acetate in dimethyl formamide at 100-110oC and atmospheric pressure was developed [14].

We have used a similar method for lower primary amine. Thus methylamine hydrochloride, 4-methoxyacetophenone, sulfur, and a base in dimethyl formamide at 60-110oC and atmospheric pressure gave the desired thioamide in 57-58% yield.

An other route of 4-methoxyphenyl-N-methylthioacetamide synthesis on heating the mixture of 4-methoxyacetophenone, N-methylformamide and sulfur at 170-180oC at atmospheric pressure according to the method [15] 35% yield was achieved.

4-Methoxyphenyl-N-methylthioacetamide is a new compound, forming colorless crystals, m. p. 89-91oC (from ethanol or from diethyl ether) [16].

We have elaborated for the thioamide obtained a new simple and efficient method of reduction with zinc dust and hydrochloric acid in ethanolic solution. N,O-Dimethyltyramine was obtained in 91% yield, which was converted to its hydrochloride, m.p. 179-181oC (from ethanol), (lit. m.p. 181-182oC [17]).

O-Demethylation of N,O-dimethyltyramine to N-methyltyramine was carried out according to earlier described method for N-acetylated compound [18] by refluxing with concentrated hydrochloric acid in the oil bath heated to 170-175oC. The yield was 98%, m. p. 146-149oC (from ethanol with a

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