Chimimanie
(Hive Bee)
03-01-03 16:42
No 412787
      N-Methylisopropylamine for MIPT and the like
(Rated as: excellent)
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This is an easy synth of N-Methylisopropylamine. This amine can be used to synthetise the MIPT family of compound (MIPT, 5-Meo-MIPT and 4-Meo-MIPT) from SN2 displacement on brominated or tosylated tryptophols. These compounds become avaiable by fast and easy fischer indole synthesis (altough 4-MeO-tryptophol is a bit harder to make).

This text is in german, it would be nice if somebee translate it.

Notiz zur Darstellung des N-Methylisopropylamins, Arch. Pharm. p644, 314, 1981

Experimenteller Teil

59g (1,0 mol) wasserfreis Isopropylamine werden unter Eiskühlung und Rühren tropfenweise mit 85.7g (1,0 mol) einer eiskalten 35proz. Lösung von Formaldehyd verstetzt. Dabei scheidet sich 1,3,5-Tris(isopropyl)-hexahydro-1,3,5-triazin 2 als Öl ab. Nach 15 min wird die Ölschicht abgetrennt und über wasserfreiem Kaliumcarbonat 12h im Kühlschrank getrocknet (Ausb. 83% d. Th.). 40 g 2 werden langsam zu einer auf -5° abgekühlten angesäuerten Suspension von 70g Zinkstaub in 200 ml Wasser unter starkem Rühren zugetropft. Gleichzeitig tropft man 320 ml konz. Salzsäure bei -5° zu. Nach beendetem Zutropfen wird noch 1h weitergerührt, vom ungelösten Zinkstaub abfiltriert und die salzsaüre Lösung in einem Dreihalskolben mit Rührer und Liebigkühler langsam zun einer 90° warmen 40proz. NaOH zugetropft. Das überdestillierende N-Methylisopropylamin [siedebereich 50-60° (760 Torr)] wird unter Kühlung aufgefangen und anschliessend über einen 30 cm Vigreux-Aufsatz fraktioniert. Die Hauptfraktion siedet zwischen 49-51° (760 Torr). Das Pikrat vom Schmp. 135° kristallisiert aus Ether/Ethanol erst nach 3-4 d aus.
Im GC geben sich Spuren von als Nebenprodukten entstehendem Isopropylamin durch eine kürzere Retentionszeit und N-Dimethylisopropylamin durch eine längere Retentionszeit als N-Methylisopropylamin zu erkennen.

 
 
 
 
    Nemo_Tenetur
(Analogue Bee)
03-02-03 21:36
No 413135
      Translation  Bookmark   

Experimental Part

To 59 g (one mole) anhydrous isopropylamine (stirred and cooled with an external ice bath), there was added 85.7 g (one mole) 35% aqueous formaldehyde solution. During the addition, an oily layer of 1,3,5-tris(isopropyl)hexahydro-1,3,5-triazine is formed.

After 15 min the oily layer is separated and dried over anhydrous K2CO3 for 12 hours in the refrigerator (4°C), yield: 83% of theory.

40 grams of the triazine is added slowly to a cooled (-5°C) acidic (no further specification of "acidic") suspension of 70 grams Zn dust in 200 ml H20 with strong stirring. During the addition, simultaneous 320 ml concentrated HCl is added, dropwise at -5°C. After complete addition, one hour further stirring, filter off the residual Zn dust and add the filtrate to a 40% NaOH solution (90°C hot) in a three-necked-RBF equipped with a stirrer and a liebig condenser. The liberated N-methylisopropylamine (b.p. 50-60°C @ normal pressure) is trapped in a cooled recieving flask and finally fractionally redistilled with a 30 cm vigreux column. The main fraction has the b.p. 49-51°C . The picrate has the m.p. 135°C but requires 3-4 days for crystallization from Et20/EtOH.

You can see in GC traces isopropylamine (shorter retention time) and N,N-dimethylisopropylamine (longer retention time).

Notes from Nemo_Tenetur:

This is a valuable synthesis. N-Methylisoproylamine is hard to get (only a few suppliers) and outrageous expensive. Five years ago I've bought 50 ml from *** for almost 90$ ! Unfortunately, the recipe gave no final yield claim, but the required chemicals are cheap, so it does pay even with a moderate final yield. The N-methyl-N-isopropyl substitution pattern is a good choice!
 
 
 
 
    Chimimanie
(Hive Bee)
03-03-03 12:33
No 413298
      Thank you
(Rated as: excellent)
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Thank you for your translation Nemo_Tenetur.

In the introduction of the article[1] they say that the total yield is 40-50% and the purity is 95%.

This is another text from the same persons:

Bequeme Darstellung von reinen N-Methylalkylaminen durch Zink/Salzsäure-Reduktion von 1,3,5-Tris(alkyl)-hexahydro-1,3,5-triazinen Mohammed Al Shaik und Herbert Oelschläger Arch. Pharm. (Weinheim) 317, 214-219 (1984)

(Convenient Synthesis of Pure N-Methylalkanamines by Reduction with Zn/Hydrochloric Acid of 1,3,5-Trialkyl(hexahydro)1,3,5-triazines.)

N-Methylalkanamines are avaiable by reduction of 1,3,5-trialkyl(hexahydro)-1,3,5-Triazines with Zn/Hydrochloric acid at -5°C using a drop-in procedure. The purity (GLC) is in the range of 95%.

They say the same synthesis can be utilised to synthetize some other N-alkyl-N-methyl-derivative from the appropriate 1,3,5-Tris(alkyl)-hexahydro-1,3,5-triazinen. Another text with this method is [3].


Table 1:
Boiling point of the N-alkyl-methylamines avaiable from the respective triazines (no cristalline picrates are obtained from these one):

alkyl= allyl:      bp 62
       propyl:     bp 62
       n-butyl:    bp 89-91
       isobutyl:   bp 78-79
       tert butyl: bp 66-69
       cyclohexyl: bp 145

Otherwise they say the N-alkyl-methylamine are also avaiable from reduction of the schiff base in anh. EtOH with PtO2 and 3 atm of H2. This way N-methyl-ethylamine is prepared in 32% yield and N-methyl-isobutylamine in 67%.

Experimenteller Teil

Synthese der 1,3,5-Tris(alkyl)-hexahydro-1,3,5-triazine

Sie erfolgt gemäss [1]. Die hierbei anfallenden öligen Hexahydrotriazine werden ohne weitere Reinigung mit Zn/Salzsäure reduziert. Zur Überprüfung der physikalischen Konstanten haben wir kleine Mengen destilliert bzw. umkristallisiert.

see table 1; Cyclohexylderivat Schmp 72-73°.

Reduktion der 1,3,5-Tris(alkyl)-hexahydro-1,3,5-triazine

Sie wird gemäss [1] durchgeführt. see table 1.

Reduktion der Schiff'schen Basen

N-Methyl-n-propylamin

58g (1mol) n-Propanal werden innerhalb 2h zu einer mit Eis/Kochsalz gekühlten Methylaminlösung (77.5 g einer 40proz. wässrigen Lösung) unter starkem Rühren zugetropft. Nach Zugabe des aldehyds wird der Ansatz noch 1h in der Kälte gerührt, in einem Scheidetrichter mit festem Kaliumkarbonat und Kaliumhydroxid (1:1) versetzt, kräftig geschüttelt und 15 min stehengelassen. Man trennt die wässrige Phase ab, tocknet die obere Aldiminschicht 2h über K2CO3 und KOH und fraktioniert anschliessend. Das Aldimin geht bei 53° über, Ausb 35% d. Th.

D8ie Hydrierung von 0.3 mol Aldimin wird bei 20° in einer Skita-Apparatur unter 3,5 atü in absol. EtOH mit vorreduziertem PtO2 durchgeführt. Die Aufnahme der berechneten Menge H2 (0.3 mol) dauert ca. 3h. Die übliche Aufarbeitung ergibt 25% d. Th. N-Methyl-n-propylamin vom Sdp. 62°.

N-Methyl-ethylamin

Analog N-Methyl-n-propylamin Aldimin: Ausb. 55% d. Th., Sdp. 28-29°. Amin: Ausb. 80% d. Th., Sdp. 32-34°. Check also ref [15]

N-Methyl-isobutylamin

Analog N-Methyl-n-propylamin Aldimin: Ausb. 65% d. Th., Sdp. 67-69°. Amin: Ausb. 67% d. Th., Sdp. 78-79°, lit.: Sdp 76-78°.

Reduktion eines Ketimins (2-Methyliminopropan)

58g (1mol) Aceton werden langsam zu einer mit Eis/Kochsalz gekühlten 40proz. Methylaminlösung (77,5g = 1 mol) zugetropft und anschliessend 30 min gerührt. Nach 24 h Stehen und Zugabe von 4 ml Methylaminlösung wird das gebildete Ketimin in einer Skita-Apparatur unter 3,5 atü bei 20° mit 0.5 g PtO2 hydriert. Nach 5 h ist die berechnete Menge H2 verbraucht und die Hydrierung kommt zum Stillstand. Die übliche Aufarbeitung ergibt 60% d. Th. N-Methyl-isopropylamin vom Sdp. 50-51°.

Literatur:

[1]: Look two post higher.
[3]: J. Graymore, J Chem Soc 1931, 1490 and 1932, 1353. 
[15]: http://www.orgsyn.org/orgsyn/prep.asp?prep=cv5p0758

It would be nice to have a translation of the experimental part....wink
 
 
 
 
    Rhodium
(Chief Bee)
03-08-03 22:48
No 414873
      Cyclic Methyleneamines. Part I.
(Rated as: excellent)
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The Reduction Products of Certain Cyclic Methyleneamines. Part I.
By John Graymore, J Chem Soc 1490 (1931)

The cyclic methyleneamines used in this investigation are those resulting from the condensation of formaldehyde with ammonia, and the monoalkylamines.

The reduction of hexamethylenetetramine with zinc in acid solution is stated by Trillat and Fayollat (Compt. Rend., 1893, 111, 628) to give ammonia and methylamine and by Delepine (Bull. Soc. Chim. 1895, 13, 136) to give ammonia and trimethylamine. It therefore seemed profitable to re-explore this field and to examine the allied compounds, the trialkyltrimethylenetriamines.

Hexamethylenetetramine, heated under reflux with an excess of hydrochloric acid, decomposed with production of formaldehyde, and the hydrochlorides of ammonia and methylamine. The hydrochlorides were obtained in relatively small yield, increasing with the time of reaction. No trimethylamine could be detected. On the other hand, hexamethylenetetramine, reduced with zinc dust in presence of an excess of hydrochloric acid, gave ammonia and trimethylamine as main products. Where the reduction was allowed to proceed slowly, or under reflux, a varying quantity of methylamine was also obtained, with in some cases a little dimethylamine. It seems probable, therefore, that the reduction of hexamethylenetetramine with zinc dust in acid solution proceeds as follows: 

HMTA + 3 H2 (-CH2NH-)3 + N(CH3)3

Trimethylenetriamine and trimethylamine being the initial products. The unstable cyclic compound would then break to give ammonia and formaldehyde in equilibrium with methyleneimine and water

CH2O + NH3 CH2=NH + H2O.

Reduction of methyleneimine by formaldehyde or by zinc and hydrochloric acid would yield methylamine with a small amount of dimethylamine (compare Werner, JCS 1917, 111, 844).

In order to discover whether any of the amines resulted from the interaction of the liberated formaldehyde with the hexamethylenetetramine remaining, the latter substance in the form of its picrate was heated with formaldehyde in alcoholic solution. Dimethylpentamethylenetetramine picrate resulted. Formaldehyde did not appear to react further with this compound, as might be expected (compare Knudsen, Ber., 1914, 47, 2694).

The trialkyltrimethylenetriamines of general formula (-CH2-NR-)3 were prepared directly by treating the primary amine either in the anhydrous state or in aqueous solution with a 40% solution of formaldehyde, with subsequent separation of the base by dehydration over caustic potash. Reduction by means of zinc dust and hydrochloric acid gave in each case the corresponding secondary methylalkylamine as a main product together with a small proportion of the primary alkylamine, the proportion of the latter decreasing with increasing molecular weight. This would seem to indicate the greater stability of the higher alkylmethyleneimines.

The results suggest that reduction is brought about in the following manner, (-CH2-NMe-)3  3 CH2=NMe,  3 CH2=NMe + 3 H2 3 CH3NHMe. Methylenealkylamine, CH2=NR, being first of all produced. Decomposition of a portion of this would give the primary amine and formaldehyde. Heated with hydrochloric acid alone, the cyclic bases break to give the corresponding primary amine together with formaldehyde.

In common with the trimethyl and the triethyl derivative, tripropyltrimethylenetriamine exhibits a strong solvent action on uric acid, and also forms additive compounds with bromine and iodine. The reduction of these compounds appears comparable with the reduction of similar compounds of the type R-CH=N-R obtained from the condensation of the higher aldehvdes with alkylamines (Stoermer and Lepel, Ber., 1896, 29, 2110). Since the reaction should appear capable of general application, the preparation of other cyclic trialkyltrimethylenetriamines is being attempted with a view fo the study of their reduction compounds.

Experimental

Reduction of Hexamethylenetetramine

Hexamethylenetetramine (20g) in cold aqueous solution was treated with zinc dust (60g), and cooled in ice while hydrochloric acid in slight excess of the calculated quantities (250ml; d 1.16) was added slowly with shaking, continued for 1/2 hour. The mixture was then warmed slowly and finally boiled for 1 hour until the odour of formaldehyde had disappeared. An excess of caustic soda having been added, a mixture of ammonia and amines was distilled into hydrochloric acid. The hydrochlorides obtained from this solution, after removal of the bulk of the ammonium chloride by extraction with alcohol, were estimated by the method of Bertheaumé, the mean of several estimations being 8g of trimethylamine hydrochlorride, 6g of methylamine hydrochloride, 20g of ammonium chloride, and a trace of dimethylamine hydrochloride.

Hexamethylenetetramine Picrate

This was obtained from its components in alcoholic solation or, better, by the addition of formaldehyde to concentrated ammonia solution in the presence of alcoholic picric acid. It crystallised in long yellow needles, mp 179°C (dec.).

Action of Formaldehyde on Hexamethylenetetramine Picrate

The picrate (5g) was dissolved in warm alcohol, an excess of formaldehyde solution (40%) added, and the mixture heated on a water-bath for 1/2 hour; reddish crystals then began to separate. On cooling, dimethylpentamethylenetetramine picrate (5g) separated in deep orange-red needles, mp 196°C (dec.).

Reduction of Trimethyltrimethylenetriamine

The base was prepared by the slow addition to an ice-cold solution of methylamine (100 parts of 33%) of an ice-cold solution of formaldehyde (70 parts of 40%). It separated as an oily upper layer on addition of stick potash, the solution being cooled in ice. After 48 hours the layer was removed and distilled (bp 166°C) over barium oxide. Yield, 80% of the theoretical.

A solution of the base in water (20g in 200ml) was cooled, zinc dust (35g) added, followed by hydrochloric acid (160ml; d 1.16), added slowly with cooling. The mixture was shaken at room temperature for 1/2 hour, heated gradually with continuous shaking to boiling (1 hour), boiled for 1/2 hour until no further formaldehyde was evolved, and then cooled and separated from undissolved zinc, The mixture of amines was isolated as crystalline hydrochlorides which were estimated by Bertheaumés method. The yield of dimethylamine hydrochloride was 24g, and of methylamine hydrochloride 10 g.

Reduction of Triethyltrimethylenetriamine

The base was prepared 90% yield by the method described above, a 33% solution of ethylamine being used. It was reduced and the reduction products were collected in hydrochloric acid as before. Hardly any formaldehyde was perceptible. T'he amines were liberated by addition of caustic soda to the solutiuon cooled in a freezing mixture. Separated, and distilled over barium oxide, they gave a little ethylamine, bp 18°C, followed by a good yield (80% of the theoretical) of methylethylamine, bp 35°C (platinochloride, mp 208°C). The picrate crystallized from alcohol in yellow needles, mp 196°C, soluble in acetone and chloroform and insoluble in ether.

Preparation of Tripropyltrimethylenetriamine

The base was prepared by the gradual addition of an ice-cold solution of formaldehyde (25g of 40% solution) to anhydrous propylamine (20g) cooled in a freezing mixture; it immediately began separating as as upper layer, considerable heat being developed. The base was also prepared from paraformaldehyde and anhydrous propylamine, The reaction being started by gentle warming, but the yield was much lower. The cyclic compound, the separation of which was completed by addition of stick potash, was distilled over barium oxide and obtained in theoretical yield (23g).

Tripropyltrimethylenetriamine urate dissolves in 8 parts of water at 15°C. It is an amorphous powder which decomposes without melting when heated.

Tripropyltrimethylenetriamine di-iodide was obtained when a solution of the base in chloroform was added drop by drop to a saturated solution of iodine in chloroform until the colour just disappeared. Evaporation yielded colourless needles, mp 85°C. Excess of iodine produces a dark red oil of variable composition.

Tripropyltrimethylenetriamine dibromide was obtained when a solution of bromine in carbon disulphide was added gradually to a solution of the base in the same solvent. The orange-red oil which immediately separated was repeatedly washed with carbon disulphide to remove uncombined bromine. It could not be induced to crystallise.

Reduction of Tripropyltrimethylenetriamine

No propylamine was obtained. The base yields an almost theoretical quantity of methylpropylamine, mp 62-64°C, identified by conversion into the nitrosoamine, bp 175°C (Ber., 1896, 29, 2110).
Methylpropylamine picrate, obtained by the addition of picric acid to the base in dry ether, crystallised slowly from a syrup after removal of the ether, in squat needles, mp 43°C, soluble in alcoholic acetone and water.
Methylpropylamine oxalate, prepared by adding an alcoholic solution of oxalic acid to the anhydrous base, separated in pearly flakes, mp 155°C.
Methylpropylamine hydrochloride, prepared in dry ether, crystallised in deliquescent plates, mp 140°C.
 
 
 
 
    Rhodium
(Chief Bee)
03-12-03 01:45
No 415886
      Cyclic Methyleneamines. Part II.
(Rated as: excellent)
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The Reduction Products of Certain Cyclic Methyleneamines. Part II.
by John Graymore, J Chem Soc 1353 (1932)

The method employed for the preparation of secondary amines (JCS 1931, 1490) has been extended to other cyclic methyleneamines.
In all the cases examined, the condensation 3 R-NH2 + 3 CH2O (R-N=CH2)3 + 3 H2O proceeds normally to give a practically theoretical yield of the cyclic base.
These bases are stable in neutral or alkaline solution, but readily decompose in the presence of acid, rapidly on warming, evolving formaldehyde and giving the corresponding salt of the original primary amine used.

They all form urates soluble in water, but the solubility of these is not so great as in the previous cases studied. The bases form oily additive products with bromine and iodine, the investigation of which is not yet complete.
Reduction with zinc dust and hydrochloric acid proceeds smoothly, the secondary alkylmethylamines being the main product, (R-N=CH2)3 + 3 H2 3 R-NH-CH3

Experimental

Triisobutyltrimethylenetriamine

20g of freshly distilled isobutylamine (bp 68°C), well cooled, were added gradually with shaking to an ice-cold solution of formaldehyde (21g of 40%). Immediate separation of an oily base took place. Caustic soda was added to complete the separation and the base was removed and finally dehydrated over barium oxide. It distilled from barium oxide as a colourless liquid, bp 255°C, having the characteristic odour of these compounds, d18°  0.8220).
The picrate crystallised from alcohol in squat prisms, mp 107°C. It decomposed in boiling water, evolving formaldehyde; isobutylamine picrate, mp 148°C, was isolated from the solution.
The oxalate, precipitated by the base from a concentrated alcoholic solution of oxalic acid, crystallised from aqueous alcohol in pearly plates, mp 165°C.

Reduction

The freshly distilled base (20 g) was dissolved in well-cooled dilute hydrochloric acid, and zinc dust (20g) added. Hydrochloric acid (110g, (d 1.16, diluted to 1 in 3) was added slowly with cooling. After 15 minutes, the mixture was very gradually heated to boiling (2 hours). Ebullition was maintained until any trace of formaldehyde perceptible had disappeared. The mixture of amines was distilled from excess of caustic soda into hydrochloric acid. Diethylisobutylamine was isolated from this solution in the form of its nitroso-derivative, bp 185-180°C (Stoermer and Von Lepel, Ber., 1896, 29, 2110), converted into the hydrochloride, mp 177°C, by heating with alcoholic hydrogen chloride, and regenerated therefrom (12g), bp 76-78°C.
The picrate crystallised from alcohol in yellow needles, mp 103°C. The hydrobromide, prepared by adding a slight excess of the base to hydrobromic acid and evaporating the solution in a vacuum, crystallised from water in needles, mp 203°C.

2,4-Dinitromethylisobutylaniline crystallised quickly from a warm solution of 2,4-dinitrochlorobenzene in alcohol on addition of a slight excess of methylisobutylaniline; mp 92-93°C after recrystallisation from hot alcohol.

Tri-n-butyltrimethylenetriamine

This was prepared from n-butylamine (20g) and 40% formaldehyde (21g) in the cold. The oily base, dried over barium oxide for 2 days, had bp 285°C and d17° 0.8550.

The picrate was obtained from alcoholic solution as a syrup which crystallised after several days, and was recrystallized from aqueous alcohol, forming needles, mp 75-70°C, slightly soluble in water. It decomposed when heated with water, evolving formaldehyde. The hydrochloride, obtained as a feathery mass from the base and hydrogen chloride in benzene, was extremely deliquescent.

Reduction

This was done, and the methyl-n-butylamine isolated, as in the case of the isobutyl compound. The nitrosoaniline was a yellow oil, bp 198°C, and the hydrochloride formed somewhat deliquescent needles, mp 170°C The recovered base (12-13g) had 90-91°C.

Methyl-n-butylamine picrate was prepared in alcoholic solution and crystallised in needles, mp 110-111°C, slightly soluble in water.

Triisoamyltrimethylenetriamine

Isoamylamine (20g) readily condensed with formaldehycle (18g of 40% solution) on gradual admixture with much cooling and shaking. Heat was evolved and the cyclic base separated immediately. It was purified as in the previous cases and obtained as a rather unpleasant-smelling oil, bp 299-300°C, d18° 0.8250, insoluble in water but soluble in alcohol and ether.

The oxalate, precipitated from a concentrated alcoholic solution of oxalic acid, crystallised from aqueous alcohol in light leaflets, mp 115°C, sparingly soluble in cold water. It decomposed in hot aqueous solution, giving off formaldehyde; isoamylamine oxalate, mp 165°C, was isolated from the residual liquor. The picrate separated from alcoholic solution as a syrup and crystallised from acetone, cooled in a freezing mixture, in tufts of needles, mp 75°C (indistinct), soluble in water and alcohol. The hydrochloride, obtained from benzene solution, was so deliquescent that its mp could not readily be determined. The urate was a white amorphous powder only slightly soluble in water. It decomposed at a high temperature without melting. Boiled with water, it decomposed, evolving formaldehyde.

Reduction

This was done as in the previous cases and gave 10g of methylisoamylamine, bp 108°C, isolated through the nitrosoamine, bp 204-205°C and the crystalline hydrochloride, mp 178°C.
Methylisoamylamine hydrobromide crystallised from an aqueous solution of the components in needles, mp 183°C, soluble in alcohol and water.

Tribenzyltrimethylenetriamine

This was prepared from 20g of benzylamine and 18g of 40% formaldehyde solution in a freezing mixture, separation of the treacly base being completed by addition of caustic soda. The base was extracted and dried (48 hours over barium oxide) in ether, distilled above 200°C, and again dried over barium oxide ; on redistillation it had bp 240°C and d15° 1.05 (yield, 80%). It is insoluble in water but soluble in alcohol, ether, and benzene.

The oxalate, precipitated from alcoholic solution and recrystallised from aqueous alcohol, formed plates, mp 135°C (dec.) Its aqueous solution evolved formaldehyde when boiled, and benzylamine oxalate, mp 201°C, was isolated from the residual liquor.

Reduction

20g of tribenzyltrimethylenetriamine were dissolved in cold dilute hydrochloric acid, 30g of zinc dust added, followed gradually by 420ml of dilute hydrochloric acid (1:3). Reduction was carried out as before and the mixed amines were collected in hydrochloric acid. The hydrochlorides obtained from the solution were dissolved in water and shaken with benzenesulfonyl chloride and sodium hydroxide, an excess of the latter being finally added, and the mixture warmed to dissolve the sulphonamide of the primary amine. The insoluble benzenesulfonbenzylmethylamide crystallised from acetone in tiny hard granules, mp 130°C, soluble in alcohol. From the filtrate, benzenesulphonbenzylamide, mp 88°C, was obtained by precipitation with hydrochloric acid and recrystallisation from acetone.

p-Toluenesulphonbenzylmethylamide crystallised from acetone in squat prisms, mp 92°C.

2,4-Dinitromethylbenzylaniline separated slowly in long yellow needles from an alcoholic solution of 2,4-dinitrochlorobenzene containing a slight excess of benzylmethylamine; mp 140°C after recrystallisation from alcohol.

The method is being extended to other primary aliphatic and aromatic amines.
 
 
 
 
    Chimimanie
(Hive Bee)
03-12-03 02:02
No 415891
      amines  Bookmark   

Yes Rhodium, but dont forget to complete the part one...winkblushwinksmile
 
 
 
 
    Chimimanie
(Hive Bee)
05-16-03 02:54
No 433441
      MET and 5-benzyloxy-MET
(Rated as: excellent)
 Bookmark   

This is the traduction of a french article:

Synthèse de nouvelles tryptamines substituées Roland Stauffer Helvetica Chimica Acta 49(3) 1966 p 1199

This article is about N-methyl-N-ethyl analogs of tryptamines. (especially this true gem:MET, N-methyl-N-ethyl-tryptamine)

The dude remarked than when quenching LAH solution of secondary amine with ethyl acetate, some tertiary amine (with a new ethyl group) were synthetised. It is old news for most bees than quenching those solution like this yield some ethylated amine, apparently because the lithium salt of the secondary amine react with the acetyl of the ethyl acetate to yield an amide which is further reduced with another LAH to the tertiary amine. I know the synthesis described here is not suitable for us, but the experimental section has some interesting tricks.

He synthetise the esters of the indole-3-acetic acid with a sulfonic Dowex resin   with good yield and then synthetise the corresponding mono-methyl amide with aqueous methylamine. The LiAlH4 reduction of this and the ethyl acetate quench afford the methyl ethyl amine and the mono-methyl amine in variable yield: the more ethyl acetate used the more ethylated amines.

If only we could find another reducing agent which could ethylate like this the amine it could become a great road to MET:

IAA --Dowex, MeOH--> IAA ester --aq MeAm--> The Amide --hopefully another reducing agent than LAH, ethylacetate--> MET

Another thing that is interesting is this pathway:

Tryptamine ---Ac2O, formic--> Formyl tryptamine --LAH, Ethyl acetate--> MET

If only I had some LAHfrown


Here we gowink:

Experimental

Benzyloxy-5-N-formyltryptamine (VII)

82ml acetic anhydride and 35ml formic acid are stirred at 50-60°C for two hours. To this solution is introduced dropwise 100g of benzyloxy-5-tryptamine in 250 mL of THF while the reaction mixture is cooled at 30°C. After 12h at RT, the THF is removed in vacuo (12 Torr), on a 30°C waterbath. A oily residue is obtained, 100 mL H2O is added and after two hours the oil crystallise. It is recrystallised in 700 mL of 50% EtOH to yield 99g (90%) of VII as white paillettes mp 99-101°C.

(Benzyloxy-5-indolyl-3)-methyl acetate

220g of  (Benzyloxy-5-indolyl-3)-acetic acid dissolved in 2L of absolute MeOH are refluxed for 6h with 20g of Dowex 50 x 8 sulfonic resin. The solution is filtered and decolorized with activated charcoal, then concentrated under a 12 Torr vacuum till the start of cristallisation, with waterbath temp not exceeding 35°C. After cooling and filtration, a yield of 200g (87%) of the ester is obtained as light pink prisms, mp 72-74°C.

N-methyl-(benzyloxy-5-indolyl-3)-acetamide (V)
 
200g of (Benzyloxy-5-indolyl-3)-methyl acetate suspended in 600mL of 40% aqueous methylamine are vigorously stirred for 12 h. After filtration, water wash and drying, 187g of uncolored crude amide are obtained, with a mp of 140-142°C. After a two hours reflux in 500 mL of benzene the non-transformated ester is eliminated and 175g of pure amide are obtained as white prisms, mp 142-143°C (ref [4] : 141-142°C).

Benzyloxy-5-N-methyltryptamine (III) by reduction of the amide V.

25g of the amide V is dissolved in 300 mL THF and introduced dropwise, at RT, in a suspension of  10g LiAlH4 in 300 mL THF. After a 10h  reflux, the excess hydride and the complex are destroyed by the slow addition, with good stirring, of 10 mL water, 10 mL of 15% NaOH and 30 mL H2O. The formed hydroxydes are essorated and washed with THF. After the evaporation of the filtrates under 12 Torr, a oily residue is obtained, which is dissolved in 100 mL MeOH. After the addition of 10g of anhydrous oxalic acid, 17.5g of III oxalate are obtained, mp 203-205°C (ref [4] : 201-203°C).

Benzyloxy-5-N,N-methylethyltryptamine (II) by reduction of the amide V.

A solution of 24g of the amide V dissolved in 300 mL THF is introduced dropwise, at RT, in a suspension of  10g LiAlH4 in 300 mL THF. After a 10h  reflux, the solution is cooled at 15°C and 50 ml ethyl acetate is added dropwise. The solution is then again refluxed for 2 hours. The excess hydride and the complex are destroyed as above with 10mL water, 100 mL 15% NaOH and 30 mL H2O. After concentration under 12 Torr until a oily residue is obtained, then dissolution in 100 mL MeOH, the oxalate of II is obtained with the addition of 10g anhydrous oxalic acid. Yield : 15 g (46%) as white needles, mp 165°C.

Benzyloxy-5-N-methyltryptamine (III) by reduction of the benzyloxy-5-N-formyltryptamine VII.

A solution of 35g benzyloxy-5-N-formyltryptamine in 150 mL of  THF is introduced dropwise in a suspension of 10g LiAlH4 in 400 mL THF. After a 10h reflux the decomposition is effectued as above with water and 15% NaOH. The oxalate is formed in MeOH with anhydrous oxalic acid. 32g (73%) of the oxalate of III is such obtained, mp 205°C.

Indole-3-methyl acetate

50g of acid indolyl-3-acetic in 500 mL of MeOH is refluxed for 4 h with 10g of Dowex 50 x 8 (dried in oven at 120°C until constant weight). After cooling and filtration of the resin, the solution is concentrated under 12 Torr at 35°C, then the residual oil is distilled at bp 180-185°C/0.2 Torr. 49g (91%) of the ester is obtained, it crystallise in benzene, mp 49°C (ref [11] : 49-50°C).

beta-(Indolyl-3)methyl propionate

50g of acid beta-(indolyl-3)-propionic in 500 mL of anhydrous MeOH is refluxed for 4 h with 10g of Dowex 50 x 8 (dried at 120°C). After cooling and filtration of the resin, the solution is concentrated under 12 Torr, the residual oil is distilled at bp 180°C/0.2 Torr. The ester obtained is crystallised in benzene to yield 45g (84%) of product as white needles, mp 81-83°C.

N-methyl-indolyl-3-glyoxylamide (VI)

In a solution of 100g of indol in 2.5L of anhydrous Et2O dried on CaH2, is introducted dropwise in one hour, with strong stirring 100 mL of oxalyl chloride, the temperature maintened below 20°C. The indolyl-3-glyoxylic acyl chloride begin to crystallise after the introduction of 1/3 of the oxalyl chloride. After the end of the addition, stirring is continued for one hour, then the chloride is filtered (145g, air dried).  It is added by small quantity in 500 ml of aqueous methylamine between 0 and 10°C. The chloride yield 125g (73%) of the amide VI, mp 222-223°C, white needles from EtOH.

N-methyltryptamine (IV)

30g of the amide VI are placed in a Soxhlet apparatus and are extracted for 6 days with 2.5 L of anhydrous Et2O containing 30g of LiAlH4 suspended. The decomposition is effectued in the cold with 100mL of THF containing 20% water, then with 1300mL H2O. After filtration of the hydroxydes and concentration of the filtrate under 12 Torr, 25g of a yellow oil is obtained. It is distilled in vacuum (bp 150-155/0.2 Torr). The distillate is dissolved in 75 mL of benzene to yield 18g (71%) of IV as white prism, mp 89°C (ref [8] : mp 89-90°C ; cfr [9] and [10] too).

Benzyloxy-5-N,N-methylethyltryptamine (II) by alkylating reduction of the benzyloxy-5-N-formyltryptamine VII .

A solution of 35g of VII in 150 mL THF is introducted dropwise to a suspension of 20g LiAlH4 in 400 mL of THF. After a 12h reflux, 35 mL ethyl acetate is slowly added, the reflux is continued for 2 h more and then the reaction mixture is decomposed with water and 15% NaOH like above. The yield is 20g (42%) of II, isolated as its oxalate, mp 165°C.

N-methyltryptamine and N,N-methylethyltryptamine (I)

45g of the amide VI are extracted in a Soxhlet apparatus with 2.5 L anhydrous Et2O, containing 45g of LiAlH4 in suspension. The extraction is done for 6 days. After cooling to 15°C 100 mL of ethyl acetate is added slowly, then the reflux is continued for 2 hours more. The reaction mixture is decomposed with water and 15% NaOH as above, the hydroxydes are filtered and the filtrates concentrated in vacuo (12 Torr). An oil is such obtained, which shown a violet fluorescence and distill between 160 and 168°C at 0.2 Torr. It is dissolved in 100 mL of MeOH and 15 g of anhydrous oxalic acid is added. A first oxalate fraction (13g) correspond to the oxalate of N-methyltryptamine (IV), as uncolored prisms, mp 178-180°C.

To the filtrate is added 50 mL Et2O and then it is cooled at -10°C. A second crop of oxalate crystallise. It is recrystallised in MeOH to yield 15g of the oxalate of N,N-methylethyltryptamine as white needles, mp 120°C.

References:

[4]  A. Stoll, F. Troxler, J. Peyer and A. Hoffman, Helv. 38, 1466 (1955).
[8]  A. Fiser, JACS 78, 3670 (1956).
[9]  M. E. Speeter and W. C. Anthony, J. Pharmacol. 14,99 (1959).
[10] T. Hoshino, Liebigs Ann. Chem. 520, 13 (1934).
[11] R. W. Jackson, J. Biol. Chemistry 88, 659 (1930).
 
 
 
 
    Chimimanie
(Hive Bee)
07-20-03 17:17
No 448644
      Dimethylamine from formaline
(Rated as: excellent)
 Bookmark   

Methylation by Means of Formaldehyde. Part I., A. Werner, J. Chem. Soc., pp844-853 (1917)
(same ref than in ../rhodium/chemistry /methylamine.html)

Experimental:

Preparation of Dimethylammonium Chloride.

The formation of the above salt in this reaction has been recently pointed out by Knudsen, but the method adopted for its preparation distinctly shows the absence of a reasonable appreciation of the probable mechanism of the changes. Thus, in an experiment designed with the object of obtaining the best yield of the secondary amine, a useless, not to say a wasteful, excess of formaldehyde was employed without any particular advantage. The following experiment, carried out on the lines of the present theory, gave a very good result.

Expt II: Dimethylamine

Two hundred grams of ammonium chloride and 400 grams of formalin were heated to 104°, as in Expt. I, and 65 grams of ammonium chloride were recovered. To the filtrate 300 grams of formalin were now added, and the solution was again heated at this stage to 115°, and maintened as nearly as possible at this temperature until no more liquid distilled. This required about three and a half hours. Since methylammonium chloride, produced during the first stage, is less easily dissociated than ammonium chloride, a higher temperature was required to bring about reaction. It was noticed that whilst a volatile liquid commenced to distil at about 52° in the first stage, 92° was reached in the second stage before any liquid distilled, which is quite in agreement with theory.

The product was concentrated by evaporation at 100° until a scum appeared on the surface of the hot liquid ; 7 grams of ammonium chloride, and 27 grams of pure methylammonium chloride were recovered from the material which had separated after cooling. The product was now heated to 120°, until a portion when cooled became a semi-solid, crystalline mass, after which it was allowed to remain for two days in a partial vacuum over sodium hydroxide. It was then treated with chloroform as described under Expt. I, and 122 grams of nearly pure dimethylammonium chloride were ultimately obtained. The final residue contained some trimethylammonium chloride, but was not further dealt with.

The yield of dimethylammonium chloride calculated on the weight of ammonium chloride which had entered into reaction (that is, 200-72=128 grams) was therefore 95.3% with the use of 700 grams of formaldehyde solution. Knudsen obtained a yield of 70% from 100 grams of ammonium chloride and 1000 grams of formalin.


Preparation of Methylammonium Chloride.

The proportions of ammonium chloride and formaldehyde (40% formalin)* recommended by Brochet and Cambier, namely one part by weight of the former, and two parts by weight of the latter, were found after several trials to give the best results. Since about 35% of ammonium chloride has always been recovered unchanged, the molecular ratios NH4CL:2CH2O required by theory are very closely represented by the above proportions.
 
Expt I: Methylamine

Two hundred and fifty grams of ammonium chloride and 500 grams of formaldehyde solution were gradually heated in a distillation flask, which carried a thermometer with the bulb well below the surface of the liquid. The temperature was slowly raised to 104°, and not allowed to rise above this point, at which it was maintened until no more volatile liquid distilled; this required about four and a-half hours. The distillate weighed 110 grams. The product was allowed to cool, and after filtration from 62 grams of ammonium chloride which had separated, was concentrated by evaporation at 100° to about one-half of the original volume. After removal of 19 grams of ammonium chloride**, the liquid was again concentrated by evaporation until a crystalline scum had formed on the surface of the hot solution.

After cooling, 96 grams of methylammonium chloride were separated ; after further concentration a second crop (18 grams) was obtained. The filtrate was now concentrated as far as possible at 100° and was left for twenty-four hours in a vacuum over sodium hydroxide, after which the semi-solid residue was digested with chloroform, when 20 grams of methylammonium chloride which had been washed with chloroform to remove dimethylammonium chloride, were obtained. The total yield was 128 grams.

From the chloroform solution, after removal of much of the solvent by distillation, 27.5 grams of dimethylammonium chloride were obtained.

A viscous residue (76 grams) which did not crystallise after remaining for a week in a vacuum over sulphuric acid, was finally obtained ; it contained Cl=40.37%. It was distilled after the addition of an excess of a 40% solution of sodium hydroxide, and the alkaline vapours evolved were absorbed in an alcoholic solution of hydrochloric acid, when a small quantity of methylammonium chloride and a relatively large quantity of dimethylammonium chloride were obtained, but no trimethylammonium chloride could be detected. Formaldehyde was also regenerated by the action of sodium hydroxide on the viscous material, which no doubt contained much tetramethylmethylenediamine hydrochloride, CH2(NMe2)2.2HCl, which require Cl=40.57%.

* Analyses of seven different samples of commercial formalin gave as a mean result 35% of formaldehyde, and in no case was a sample found to contain 40%. The highest value was 37.4%, the lowest 33.2%.

** Ammonium chloride is very sparingly soluble in a concentrated solution of methylammonium chloride, and consequently its separation from the later salt is very sharp.



Really, I dont get it why people hydrolise expensive DMF when cheap and easily accessible formaline give a great yield of dimethylamine.laugh
 
 
 
 
    Noid
(Hive Bee)
07-28-03 05:33
No 450289
      Good reads :)  Bookmark   

Could you get Dimethylamine by replacing the Formalin with Paraformaldehyde? Is it the same way you would go about making methylamine, but heating @115? Why stop at 104 then?

100% _______
 
 
 
 
    Chimimanie
(Hive Bee)
07-28-03 13:08
No 450362
      Maybee  Bookmark   

Maybee paraformaldehyde could bee used, but its not 100% sure...

In ../rhodium/chemistry /methylamine.html there is some reaction with it, but this part:



With an excess (4 moles) of formaldehyde, enough water and a reflux temperature of 115°C, dimethylamine is the main product, as the temperature rises, more dimethylamine is formed. Dry heating of paraformaldehyde and ammonium chloride produces trimethylamine through reaction of dimethylamine with formaldehyde, giving rise to tetramethylmethylenediamine and formic acid, and the base further reacts with HCl, giving trimethylamine hydrochloride and methyleneimine hydrochloride.




Say you need water to make dimethylamine otherwise trimethylamine is formed.

Otherwise, they stop at 104° to put some more formaldehyde, as one more eq is needed, and to filter off the remaining NH4Cl, while the methylammonium chloride stay in solution, for they dont want the formaline they just put react with NH4Cl to yield methylamine, they want it to react with CH3NH3Cl to make dimethylamine.

see the illustrative figures at Rhodium's methylamine document.

You could try it, with some water and at 115°, but the reaction woulds surely needs some tweaking... better stay with the above procedure, which is optimized for dimethylamine, as you realise minor change can make great difference in products and yields.

BTW formaline is really cheap and OTC, ask your local pharmacist (not our's wink), say you found some kind of dead reptile and wanna put it in a nice vase in your room, and you need formaline to put it in. smile

 
 
 
 
    Noid
(Hive Bee)
07-28-03 21:26
No 450437
      :)  Bookmark   

Thank's Chimimanie!
 
Im sure it is possible, but who has time for the math.. the above is proven to work, so if it's done, thats the way it will be done.

I have never sceene fomaline OTC, but heres some uses that may help other bee's:

Formaline is widely used in:

paper industry for improving paper strength and quality;
in tanning industry - for leather tanning;
in textile industry - for improving crease - and shrink - proofing properties;
in agriculture - for treatment of seeds and roots, desinfection of soil and stock buildings;
in medicine - as a disinfectant.

100% _______