Author Topic: Fisher Tryptamine Synthesis - is this right?  (Read 6165 times)

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  • Guest
Fisher Tryptamine Synthesis - is this right?
« on: July 20, 2002, 10:20:00 AM »
Check out

Patent US5607957


Patent US5510359


Patent US5602162


In the steps where they condense 4-chlorobutanal acetal with a phenylhydrazine, the product is directly the tryptamine - is that possible without an external amine source?

The atoms add up all right, but I couldn't imagine that the little ammonia split off from the hydrazine in the reaction would be enough to aminate the resulting 3-(2-chloroethyl)-indole...


  • Guest
Yes, it is possible
« Reply #1 on: July 21, 2002, 09:52:00 PM »
Method of tryptamine producing via phenylhydrazine and gamma-chlorobutanal in EtOH is described in a russian book "Syntheses of getherocyclic compounds" at 1972. Ammonia is produced in a study of Fisher's rearrangement.
If you are interesting, I can translate the manual from russian and post it here ;) .
But it is more interesting to replace gamma-chlorobutanal with gamma-N,N-dimethylaminobutanal :)  in this synthesis.

With best regards,
Dennis Prochko aka Wolf


  • Guest
It certainly is. I just find it sad that there ...
« Reply #2 on: July 22, 2002, 02:25:00 AM »
It certainly is. I just find it sad that there are no easy route to form 4-chlorobutanal or its acetals... Most seem to require rosenmund reduction of the corresponding acid chloride, or alternatively requires the synthesis of 4-chlorobutanal (which easily reverts to THF), and then oxidizing this to the aldehyde.


  • Guest
URFSE hehe
« Reply #3 on: July 22, 2002, 08:15:00 AM »
UTFSE, there is one (unconfirmed) extremely simple published synth of it (I can't remember what it was, but I can search my papers if you can't find it here). And you can buy the (dimetyl-) aminobutyraldehyde acetal.


  • Guest
You mean the one I found which used formic ...
« Reply #4 on: July 22, 2002, 11:05:00 AM »
You mean the one I found which used formic acid/NaHCO3/CHCl3? Yes, that's the problem - it hasn't been confirmed to work with this substrate in particular. And I don't remember if the starting material was the alcohol or the acid either.


  • Guest
« Reply #5 on: July 22, 2002, 04:27:00 PM »

I just find it sad that there are no easy route to form 4-chlorobutanal or its acetals...

What about this way:
a) GABA +HCHO/HCOOH -> gamma-N,N-dimethylaminobutyric acid
b) gamma-N,N-dimethylaminobutyric acid + EtOH -> gamma-N,N-dimethylaminobutyric ethylic ether
c) gamma-N,N-dimethylaminobutyric ether +Na/iPrOH -> gamma-N,N-dimethylaminobutanol
d) gamma-N,N-dimethylaminobutanol + K2Cr2O7/H2O (or other mild oxydizer) -> gamma-N,N-dimethylaminobutanal

or, gamma-N,N-dimethylaminobutyric acid + SOCl2 -> chloroanhydride (+ LAH) -> gamma-N,N-dimethylaminobutanal

With condensation gamma-N,N-dimethylaminobutanal with phenylhydrazine in EtOH at presence of phosphoric acid we can obtain DMT  :) . And when replace phenylhydrazine with 3-hydroxyphenylhydrazine... m-m-m... it is honey  ;D

With best regards,
Dennis Prochko aka Wolf


  • Guest
Another possibility for this so wanted aldehyde
« Reply #6 on: December 07, 2002, 12:25:00 PM »
Starting from 1,3 dichloropropane and doing like for 1,4 dichlorobutane:


Sodium iodide was refluxed in acetone solution with a three molar proportion of 1,4-dichlorobutane until less than 3% of the iodine remained in the inorganic form (five to six hours). Fractional distillation gave a 71% yield (based on the sodium iodide) of 1-chloro-4-iodobutane, bp 93-94.5°C (17 mm), of 94% purity. (The impurity is most probably unreacted dichlorobutane, and the product is used without further purification).

or :


 In an unoptimized first experiment, decolorized n-BuI (368g, 2.00 mol), 1,4 dichlorobutane (190.5g, 1.50 mol), and Bu4NI (5.5g, 15 mmol) were heated together (in a system fitted with a fractionating column and pot and head thermometers) to 105°C; little distillate appeared. Addition of Bu4NBr (4.9 g, 15 mmol) and heating from 105 to 141 °C over 6 h gave 49 mL of nearly pure n-BuCl (NMR), bp 75-76 °C. The product mixture, on washing with very dilute aqueous NaHSO3 (2 x 250 mL), went from dark red to yellow-orange; pressure filtration through flash grade silica gel (6 in.) decolorized it. Fractionation (first at 1 atm and then at ca. 100mm) yielded, as a middle fraction, 109g (0.50 mol, 75% of theory) of >97% pure chloro-iodo-butane, bp 115-116 °C. Early fractions and pot material were recombined for use in the next experiment.

1-Chloro-4-iodobutane (CIC4I; Second

 Leftovers from the above experiment were mixed with decolorized n-BuI (92 g, 0.5 mol), CIC4CI (63.5 g, 0.5 mol), and Bu4NI (7.5 g, 20mmol). Heating from 25 to 163 °C over 1.5 h (apparatus as before) gave 58 mL of distillate, maximum bp 74 °C. Workup of the pot material as before gave a colorlesS filtrate containing ClC4CI, ClC4I, and IC4I, nearly 1:4:4, which afforded 104.5g (0.48 mol, >95%) of >98% pure ClC4I on fractionation. Other fractions and pot material (all nearly colorless) were saved for further equilibration.

Then doing a grignard on this 1-chloro-3-iodopropane like on 1-bromo-4-chlorobutane and transform it to the acetal or aldehyde:


The reaction of bromochlorobutane with magnesium yields chlorobutylmagnesium bromide which, when treated with diethyl phenyl orthoformate yields 5-chloro-1,1-diethoxypentane (70% yield)

The aldehyde is obtained with DMF of course.

And then swap the Cl with dimethylamine like the other preparation

Sorry guys :-[ , I made a mistake >:( : forgot that the aldehyde/acetal from a grignard has one carbon added, it is for that that my ref were on dichlorobutane and not dichloropropane! I will try to fetch others ref for the preparation of 1-chloro-3-iodo-propane! ;)


(1) JACS (i think), vol 70, may 1948, 1699 (authors: Kamalludin Ahmad and F M Strong)
(2) J. Org. Chem. vol 53, no 6, 1988, p 1333
(3) Bull Chem Soc Japan, vol 49(7), 1989-1995 (1976)


  • Guest
Specially for the chief ! ;-)
« Reply #7 on: December 10, 2002, 09:29:00 AM »
Just a thought, but all looks OK:

GBL ---> y-hydroxybutyraldehyde --(HCl)--> 4-chlorobutanal

Patent GB701220

Thirty ml of a solution of approximately 80 4.0 g lithium aluminum hydride in 100 ml of dry tetrahydrofuran was added to the lactone solution with stirring over a twenty minute period The reaction mixture was maintained at a temperature of 85 -10 to -15 C, during the addition of the reducing agent After all the lithium aluminum hydride had been added, stirring was continued while the reaction mixture was allowed to gradu 90 ally warm to room temperature ( 20-25 C.) Approximately two-thirds of the solvent was evaporated under reduced pressure and the residual oily semi-solid product was poured into ice containing 95 0.055 moles of sulfuric acid The product was extracted into ether The ether extract was washed with a saturated solution of sodium sulfate (in water) to remove excess sulfuric acid, dried, and 100 distilled The product, consisting of the equilibrium mixture of a methyl-8hydroxyeaproaldehyde (I) and its cyclic hemiacetal form, 2 hydroxy 3,6 dimethyl tetrahydro-( 1,4 H)-pyran (IA), 105 distilled at a temperature of 30-40 C, under a pressure of 0 3 mm A yield of 8.4 g equivalent to 64 5,%/ of the theoretical yield was obtained.

BTW, they mention possibility of using Na amalgam instead LAH - just say that doesn't work on all lactones (they don't mention GBL specifically in the examples, which leads me to suggest that sodium CAN bee used in this case).

So, d'you like my scheme? Any potential obstacles? Would the reaction of this aldehyde with conc. HCl run smoothly, and what conditions would bee needed, you think?


P.S. Mmmmmmmm, look what i found. No LAH, huh - just plain ol' THF and chlorine (bromine possible - see Example 10).

Patent US3074964

Example 1.

Into a solution of 54120 parts of tetrahydrofuran in 184500 parts water there was passed w/stirring and cooling to 25-30 C clorine at a rate of about 15 parts per minute ubtil 5330 parts had been reacted. The rxn soln was neutralized w/CaCO3, whereupon the mixtr separated in two layers. The upper layer after removal of solvt was distilled at 10mmHg giving a colorless liquid boiling at 55-58 C (gamma-hydroxybutyraldehyde) and another liquid boiling at 82-86 C (GBL).

No yield given. In Example 3 (slightly different) they say ~10% yield of y-OH-butyraldehyde, ~60% GBL. Generally, the patent is mainly concerned w/making GBL (yes, goddamit, GBL) - and i can't figure what kind of conditions would favor formation of our aldehyde (although, on 2nd thought it appears to bee lower conc THF AND higher conc of acid). Nevertheless... Even if you got 10% yield, hey, who cares - it's just THF and bromine!

Oh, yeah. The max yield of GBL they got is 77% ;D  I think i'll post a link to this into that not-so-old NaBrO3/THF/GBL thread ;D


  • Guest
Sorry, guys...
« Reply #8 on: December 10, 2002, 09:47:00 AM »
Guess that the last step of my proposed synth won't work, here's what they say (

Patent US4691062

): ...It is already known to produce 4-chlorobutanal by hydrogenation of 4-chloro-butyric acid chloride in the presence of a poisoned noble metal catalyst (J. Am. Chem. Sec. Vol. 73 page 1365 (1951)) or in the presence of an alloy catalyst (German OS No. 2506157), yield of 4-chloro-butanal, however, by these known processes is relatively poor."
And go on to describe the rxn of y-hydroxybutyraldehyde dimetyl acetal with CCl4 and Ph3P as catalyst (but, OTOH, if you have triphenylphosphine, that would bee a great method, IMHO).

I mean, if it was as simple as reacting the aldehyde with HCl, they certainly wouldn't go into that much trouble (but will anyone bother to explain me, just WHY it won't work? PLEASE!)

But here's some useful info on 4-chlorobutyryl chloride reduction, looks quite nice i dare say:

Patent US4036877


95 g. of activated carbon of fine grain was purified for 2 hours at a temperature of 100 DEG -120 DEG C. in a vacuum of 20 torr and then impregnated with a solution of 7.5 g. of PdCl 2 and 0.537 g. of CuCl 2@. 2H2 O in 8 ml. of concentrated hydrochloric acid to prepare a catalyst containing 4.5 % by weight of palladium and 0.2 % by weight of copper. The impregnated carrier was neutralized and washed with distilled water and subsequently reduced with hydrogen or sodium borohydride. After washing the catalyst to neutrality it was dried. The operation could be carried out without any special measures since the obtained catalyst was pyrophoric to a reduced extent only.

6 g. of the catalyst prepared in this way was transferred into a flask equipped with a stirrer and a gas inlet tube. On adding 200 ml. of xylene, hydrogen was allowed to bubble through the liquid at a rate of 30 liters/hour, and under intensive stirring 25 g. of salicylic chloride was added at 70 DEG C. The temperature was raised within 30 minutes to 83 DEG C. and bubbling of hydrogen was continued until the development of HCl gas was terminated (for about 4-5 hours). The catalyst was filtered off the reaction mixture, the solvent was evaporated and the aldehyde distilled in vacuum. The amount of the pure product was 15.6 g., corresponding to a yield of 80 %.

In Example 16 they mention 4-chlorobutyryl chloride specifically, yield - 65% :)



  • Guest
« Reply #9 on: December 10, 2002, 11:36:00 AM »
Chlorination of aliphatic alcohols with HCl requires a lewis acid catalyst and/or elevated temperatures, and under those reaction conditions the aldehyde will also self-condense. Protecting the aldehyde function as the acetal doesn't help either, as acetals aren't stable in acid solutions.

Swern oxidation of 4-chlorobutanol (DMSO/Et3N/(COCl)2) at sub-zero temperatures yields 85% 4-Chlorobutanal according to Organic Letters 2(17), 2571 (2000), but they have no detailed experimental section.

Patent US4691062

was really great, and to me it looks like one of the most worthwhile preparations I've seen. Here follows example 1 from that patent:

129 grams (0.96 mole) of 1,1-dimethoxy-4-hydroxy-butane were slowly dropped into a solution of 315 grams (1,2 moles) of triphenylphosphine, 67.2 grams of quinoline and 2.9 grams of triethylamine in 362 ml of carbon tetrachloride at 20°C. with cooling.

After the end of the addition, the temperature increased during the post reaction to about 60°C., whereby triphenylphosphine oxide gradually fell out as a white precipitate. The reaction mixture was stirred for a further two hours, cooled to 20°C. and filtered. The filtrate was then distilled under reduced pressure at 18 mbar. The desired 1,1-dimethoxy-4-chloro-butane passed over at 68°C. The yield, based on the 1,1-dimethoxy-4-hydroxy-butane employed was 123 grams or 84% of theory.

This was dropped into 1 liter of 0.2N sulfuric acid at 50°C. and stirred further for two hours. After cooling to 20°C. the organic phase was separated off, the aqueous phase extracted 3 times, each time wth 200 ml of methylene chloride, the combined organic phases washed neutral with sodium carbonate solution, dried over magnesium sulfate and distilled at 50 mbar. The desired 4-chloro-butanal passed over at 74°C. The yield was 80 grams or 93% of theory.


  • Guest
Hypothetic possibility (+ a synthesis of indol)
« Reply #10 on: December 11, 2002, 02:57:00 PM »
Oh my I would like to have this 4-dimethoxy butanol ! Can someone find a nice ref without those paladium salt!

(BTW good work Antoncho and Rhod! I think this tryptamine synth is one of the best (the other one as not been posted here now AFAIK, I will change that very soon! STAY TUNED!  HINT: check this patent:

Patent FR2261271


Patent DE2344919

) if we can have an easy synth of this aldehyde)

The route I am thinking now start from 4-chloro-butyronitrile, accessible and not to expensive, (although the chlorobutyrylchloride is the more cheap starting material AFAIK (Oh can someone find a good ref without all this hard to do reduction of this acid chloride!)), and reducting the nitrile to the aldehyde with stannous chloride. The yield are usually quantitative, but I have no clue if it work with a molecule chlorinated like this 4-chlorobutyronitrile. Another synthesis of indole is discussed here too.

Here we go:

A New Synthesis of Aldehydes. - By HENRY STEPHEN. (Can't give the ref, sorry!  :-[ )

The ref is possibly J.Chem.Soc. 127, 1874 (1925) /Rhodium

THE basis of this new method is the conversion of a nitrile through the imino-chloride (which need not be isolated) into an aldehyde with the same number of carbon atoms. The most suitable reducing agent is anhydrous stannous chloride * dissolved in ether saturated with hydrogen chloride. Finely powdered, anhydrous stannous chloride (1.5 moIs.) is suspended in dry ether, which is then saturated with dry hydrogen chloride until the mixture separates into two layers, the lower viscous layer consisting of stannous chloride dissolved in ethereal hydrogen chloride. The nitrile (I mol.) is now added with vigorous shaking and, after a few minutes, separation begins of a white, crystalline aldimine stannichloride, (R-CH=NH,HCI)2,SnCI4.

The course of the formation and reduction of the imino-chloride is therefore as follows: R-CN + HCl -> R-CCl=NH; R-CCl=NH + SnCl2 + 2HCl -> R-CH=NH,HCl + SnCl4. After removal of this salt the ether may be again employed for another preparation. The salt is readily hydrolysed by warm water, and the aldehyde formed may be removed by distillation with steam or extraction with a solvent.

The method is applicable to aliphatic and aromatic nitriles, and the yields are usually almost quantitative. As the rate of deposition of the stannichloride varies in different cases, it is advantageous to allow at Ieast two hours for completion of the reaction.

3,4,5-Trimethoxybenzonitrile and other nitriles which are only sparingly soluble in cold ether may be dissolved in chloroform and the solution added to the reducing agent.

o-Toluonitrile and alpha-naphthonitrile give only small yields of the respective aldehydes. This is no doubt due to steric hindrance, of which the two nitriles form well known examples; both, for instance, fail to give imino-ethers (Pinner, " Die Imidoäther und ihre Derivate," 1892, pp. 4,81), for the formation of which an imino-chloride is essential.

A special application of the method is the formation of indole by reduction of o-nitrophenylacetonitrile; sufficient reducing agent is employed to reduce both the imino-chloride and the nitro-group :
(nice picture : the o-nitrophenylacetonitrile is transformed in the amino-aldehyde which cyclise to indole)
(compare Pschorr, BeT., 1910, 43, 2543).



Octonitrile was prepared by warming a solution of octoamide in thionyl chloride on the waterbath for 30 minutes and removing the excess of thionyl chloride under diminished pressure. The residue of nitrile (b. p. 87° /10 mm.) was almost pure and the yield quantitative. The method has been applied to the amides of myristic, palmitic, and stearic acids with equally good results.

Octonitrile (25 g.) was brought into reaction with stannous chloride (57 g.) in dry ether (200 c.c.), saturated with hydrogen chloride as described above. The aldehyde produced by hydrolysis of the stannichloride was isolated by distillation with steam and extraction with ether. It was obtained as a colourless oil, b. p. 65°/11 mm., having a strong lemon-like odour. Prepared by the usual methods and crystallised from methyl alcohol, the oxime was obtained in fine, silky needles, mp. 60°, the semicarbazone in needles, mp 98°, and the p-nitrophenylhydTazone in bright yellow needles, mp 80°.

* The anhydrous stannous chloride for these reactions was prepared by heating the crystalline variety until the temperature reached 180°. The product contained some stannous oxide, but this appears to be insoluble in ether saturated with hydrogen chloride. A convenient and rapid method for preparing pure anhydrous stannous chloride is to dissolve the fused mass obtained as above in pyridine. Solution takes place with evolution of heat and the insoluble stannous oxide is then filtered off. Tho filtrate deposits fine, white needles of a double compound, SnCl2,2C5H5N. When the double compound is heated under diminished pressure the pyridine is removed ; the residue is anhydrous stannous chloride.


  • Guest
DMT synthesis using 4-chlorobutanal
« Reply #11 on: December 11, 2002, 05:01:00 PM »
The above patent is also available in english:

Patent GB1438365

The best reference on synthesis of DMT using 4-chlorobutanal is without question

J. Org. Chem. 59, 3738-3741 (1994)



  • Guest
(5MeO)-Tryptamine from malonate or acetoacetate
« Reply #12 on: December 25, 2002, 03:14:00 AM »

This is a variation of the fisher reaction but instead of using the 4-chloroacetal it use 3-chloropropylmalonate(or the chloropropyl derivative of acetoacetate). See also the above cited patent for that method, as well as some future posts in this thread, when I will have the time to write them. US bee: beware, the malonic and acetoacetic esters are watched (Why?).

Note: the various references cited and synthesis of ethyl 2-acetyl-5-chloropentanoate were on the last sheet which I lost, I may post them later, sorry  :-[ ...

A New Route to Tryptamines, Santay, Szabo, Kalaus, Synthesis, may 1974, 354.

We have now developed a new versatile synthesis of tryptamine and its 5-alkoxy derivatives using the Japp-Klingemann reaction[3] and requiring only cheap and easily available starting materials.

Diethyl 3-chloropropylmalonate (1) [4] was partially hydrolyzed and the monocarboxylic acid formed during the hydrolysis was coupled with diazotized aniline without isolation.The reaction furnished a red oil which was then heated in boiling alcohol (preferentially butanol). Alkaline hydrolysis of the ester 4 (tryptamine with a carboxethyl group at position 2), R = H (position 5), obtained yielded the free carboxylic acid 5, R = H, which was easily decarboxylated in good yield in boiling hydrochloric acid[5]. The overall yield is more than 30% based on 1.

The reaction was also performed with diazotized 4-methoxy-aniline (2,R = OCH 3). In this case, the use of sulfuric acid in the decarboxylation step is preferred to hydrochloric acid to avoid ether cleavage.

In the above reaction, both nitrogen atoms of the diazotized aniline are utilized, one for building up the indole ring, the other for formation of the amino group, without any reduction taking place.

Similar results were obtained using ethyl 2-acetyl-5-chloro-pentanoate (3) in place of 1. Compound 3 was prepared from ethyl acetoacetate by alkylation with 1-bromo-3-chloro-propane.


2-Ethoxycarbonyltryptamine Hydrochloride (4; R = H):

A solution of potassium hydroxide (6.4 g, 0.11 mol) in dry ethanol (70 ml) was added dropwise, with exclusion of moisture, to a stirred solution of diethyl 3-chloropropylmalonate (1; 23.7 g, 0.1mol) in dry ethanol (70 ml). Stirring was continued for 2 h. Meanwhile, a solution of benzenediazonium chloride (2, R = H) was prepared as follows. Aniline (9.3 g, 0.1 mol, freshly distilled) was dissolved in water (100 ml) and conc. hydrochloric acid (27 ml). A solution of sodium nitrite (7.0g, 0.11 mol) in water (15ml) was added gradually while maintaining the temperature at 0-3°. After completion of the diazotization, the pH of the solution was adjusted to 6 by the addition of 10% aqueous sodium carbonate ( ~77 ml,. the temperature being kept below 0°.
The alkaline solution of 1 was cooled to -5° and the solution of the benzenediazonium chloride was added with stirring. The pH of the mixture was then adjusted to 7.4-.7.5 by the addition of 10% aqueous sodium carbonate ( ~15 ml). The mixture was kept under nitrogen for 1h at 0° , acidified with acetic acid to pH 6, and left at room temperature overnight. The solution was then diluted with water, and the precipitated dark red oil was extracted with dichloromethane. The organic phase was washed with 2N sodium hydroxide. then with water (3 x), and dried with magnesium sulfate. After evaporation of the solvent in vacuo, the dark red residue (24.0 g) was heated in boiling butanol ( 160ml) containing 4 drops of water for 24 h under nitrogen. When the solution was cooled to 0° , the product crystallized; yield: 9.6g. Concentration of the mother liquor to .half of its volume afforded a further 0.4g or product; total yield: 10.0g (37%); m.p. 238 ; after recrystallisation from ethanol, m.p. 243-244 .

Tryptamine (6, R=H):

3-(2-aminoethyl)-indole-2-carboxylic Acid (2-carboxytryptamine: 5, R = H):
A solution of 2-ethoxycarbonyltryptamine hydrochloride (4, R = H; 10.0 g. 0.037 mol) in 4N aqueous sodium hydroxide (100 ml) was refluxed for 2 h, then cooled to 0°C , and acidified with acetic acid yield: 7.6g (99%); m.p. 244 (from aqueous ethanol) Ref (5), m,p. 241-242 ).

Tryptamine (6, R=H):
A solution or 5, R=H (5.Og, 0.024 mol), in 15% sulruric acid ( 100 ml) was refluxed for 4 h. The mixture was then allowed to cool and was basified to pH 9 with conc. aqueous sodium hydroxide, The precipitated crystals were separated (2.8g). The mother liquor was extracted with chloroform and the extract evaporated to give a second crop of tryptamine (0.3g): yield: 3.lg (80%); m.p. 118-120. Upon acidification of the mother liquor. 0.5g  of starting material (5, R = H) was recovered.

2-Ethoxycarbonyl-5-methoxytryptamine Hydrochloride (4;R=OCH3):

The compound was prepared from diethyl 3-chloropropylmalonate (1; 11.9 g, 0.05 mol) following the procedure described above for 4, R = H, except that 4-methoxyaniline was used in place of aniline; yield: 2,5g (17%); m.p. 225 (from ethanol).

5-Methoxytryptamine (6, R=OCH3):

3-(2-Aminoethyl)-5-methoxyindole-2-carboxylic Acid (2-Carboxy-5-methoxytryptamine;5,R=OCH3):
The compound was prepared by hydrolysis of 4, R = OCH3, as described above; yield: quantitative; m.p. 247-248' (Ref(5), m.p. 246-248°).

5-Methoxytryptamine (6, R=OCH3):
Compound 5, R=OCH3, was decarboxylated as described above; yield: 75% ; m. p. 120-121.


  • Guest
6-Br-Tryptamine from chloropropyl diethyl malonate
« Reply #13 on: December 25, 2002, 12:59:00 PM »
This one show us that we can't prepare 4-substituted tryptamine by this method, only the second possible product,  the 6 isomer, is formed. So we can't synth psylocin like that. In fact all the ref I have on this reaction are only on tryptamine or a 5 substituted tryptamine, never a 4 substituted :( . The yields are lower too than with a 5 subst tryptamine. So this example show the limitation of the method. Next post: some ref with dimethylaminopropyl oxobutanoate!  :)  ;)  

Marine Alkaloids. 9. Synthesis of 6-Bromotryptamine. C. Gron and C. Christophersen. Acta Chem Scandinavica, 710, 1984, B38, 8

The 3-bromophenyl-diazonium ion was easily obtained by diazotation[6] of 3-bromoaniline prepared by reduction[7] of 3-bromonitrobenzene[8]. Japp-Klingemann reaction [9] of the diazonium ion with diethyl 3-chloropropylmalonate under basic conditions gave a 10 % yield of the indole I (Scheme 1) crystallizing with one molecule of ethanol. Saponification of 1 produces 2 in 80 % yield. Several attempts to decarboxylate 2 gave unsatisfactory results, however, a 80 % yield of 6-bromotryptamine (3) was finally obtained by careful acid catalysed decarboxylation. The overall yield of 6-bromotryptamine (3) from 3-bromoaniline was 6.4%.

The a priori possibility of ring closure ortho to the bromo substituent, producing the 4-bromo isomer of 1, was excluded by analysis of the lH-NMR data presented in Table 1. Evidence for the concommitant formation of the latter isomer was not encountered in any stage of the synthesis.



6-Bromo-2-carbethoxytryptamine hydrochloride (1):

1 was prepared by reaction of diazotized 3-bromoaniline (17.2 g)[6], obtained by reduction [7] of 3-bromonitrobenzene[8], with 3-chloropropyl-malonic acid diethylester (23.7 g) [13] in ethanolic potassium hydroxide. The resulting red oily product was refluxed in butanol (160 ml) with a few drops of water under nitrogen for 24 h. After cooling the product was isolated and recrystallized from ethanol (90 %) yielding 10 % of 1. EtOH m.p. 192 °C (subl.). Successive recrystallization from hydrochloric acid (0.1 M) or sublimation in vacuo (190 °C) gave analytically pure 1 m.p.114-117 °C.
Purification of the azo compound resulting from the coupling between the diazonium salt and the malonic acid ester by column chromatography (silica gel, hexane-methylene chloride) did not improve the yield of the ring closure reaction.

6-Bromo-2-carboxytryptamine (2):

2 was obtained by saponification of 1 (2.0 g) by refluxing for 24 h in ethanolic sodium hydroxide (25 ml, 2 M plus 5 mI EtOH) under nitrogen. The precipitate formed by acidification (pH 5) with acetic acid at 0 °C was recrystallized from ethanol (90 %) to give 80% 2, m.p. 250-251°C.

6-Bromotryptamine (3):

3 was prepared by refluxing for 7 h a solution of 2 (1.0 g) in sulfuric acid (20 ml, 4 N) under nitrogen. Cooling below 0 °C followed by basification with saturated sodium hydroxide solution, filtration and washing with water gave a product which after redissolving in sulfuric acid (20 ml, 4 N) and precipitation by addition of saturated sodium hydroxide solution gave 80 % pure 3 m.p. 120-120.5 °C.

[6]: Szantay, Cs., Szabo, L. and Kalaus, Gy. Synthesis (1974) 354
[7]: Speekman, B.W. and Wibaut, J.P. Rec. Trav. Chim. Pays-Bas 61 (1942) 383
[9]: Japp, F.R. and Klingemann, F. Ber. Dtsch. Chem.-Ges. 20 (1887) 2942
[13] Fischer, E. and Bergmann, M. Justus Liebigs Ann. Chem. 398 (1913) 96


  • Guest
Proposed synth for 4-dimethylaminobutanal acetal
« Reply #14 on: January 10, 2003, 05:19:00 PM »
Hello all!

Well I wanted to post this for some time but had not enough time to do it, but now it is:

A proposed Synthesis of the 4-dimethylaminobutanal acetal, this very useful chemical for all tryptamine fiends.

Well I give a ref for the synthesis of the 4,4-Dimethoxybutanal. This ref is not hard to do and pretty scalable. From it you can form the enamine with dimethylamine for instance and reduct it to the tertiary amine with one of the know method. Although I have no specific ref for this second transformation, I am pretty sure it is doable, I think the acetal will be stable to this transformation.

The synthesis of the 4,4-Dimethoxybutanal is simple but require an ozone generator. There are methods to build such  generator on the hive, UTFSE. The rate of this ozone generator must be higher than that of the models to desodorise marijuana smoke though, because 2 molar equivalent of ozone are needed for each mol of the desired aldehyde. First exactly one molar equ is needed to form the first aldehyde from the cheap and available 1,5 cyclooctadiene. To know how much time of ozonolysis is needed, you must perform the complete ozonolysis on a smaller scale, after two eq of ozone is passed the solution turn blue, indicating free ozone. You multiply that time by the relative quantity of reactant for the real ozonolysis and divide it by two as only one eq is needed. All of the parameters that define your flow of ozone must stay the same as you may doubt  ;) . The second ozonolysis is make in different conditions to make the desired dimethoxy acetal in situ, the diethoxy acetal give not a good yield (82% vs 48%).

If the reductive amination work good thats an easy and cheap way to make that stuff.

A Convenient Preparation of 4,4-dimethoxybutanal by Ozonolysis of 1,5-Cyclooctadiene. Pan Li, Jianwu Wand and Kang Zhao. Pan Li, Jianwu Wang, Kang Zhao

The article as some reviews of different synthesis of this compound with various ref as well.

4,4-Dimethoxybutanal (1a):

The relative rate of ozonolysis was tested by a small scale diozonolysis. A solution of 1,5-cyclooctadiene (8) (1.0 g, 9.2 mmol) in 10 mL of methylene chloride and 10 mL of methanol was ozonized at -78 °C. After 18 min,[7] the solution turned blue, indicating the complete ozonolysis. Under these conditions, a solution of 1,5-cycloocta-diene (8) (15.0 g, 138.6 mmoli in 150 mL of methylene chloride and 150 mL of methanol was ozonized at -78 °C. After 135 min of ozonolysis,[7] TsOH.H20 (2 g, 10.5 mmol) was then added. After the solution was stirred at room temperature for 2 h, dimethyl sulfide (15 mL) was added, and this mixture was stirred at room temperature overnight. After workup with queous NaHCO3 and CHCl3, the crude product 9 was treated with ozone at -78 °C until the solution turned blue. Dissolved ozone was removed by flushing the solution with argon. Dimethyl sulfide (15 mL) was then added. After the solution was stirred at room temperature for 3-4 h, the solvents were removed in the hood by distillation. The residue was dissolved in diethyl ether (250 mL) and washed with water (2 x 100 mL). After the removal of diethyl ether by evaporation, the residue was purified by vacuum distillation (69-72°C, 10 mmHg) to give 4,4-Dimethoxybutanal (1a) (30g, 227.0 mmol, 82% overall yield) as a colorless oil.

[7] The reaction time depends on the setup of ozone generator.


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Synthesis of 4-Chlorobutanal and its derivatives
« Reply #15 on: January 25, 2003, 02:40:00 PM »
JACS 95, 2656 (1973)

The Rosenmund reduction of 4-chlorobutyryl chloride was carried out as previously described*. A high flow rate (>200 ml/min) of hydrogen or of a mixture of hydrogen and nitrogen had to be maintained in order to prevent an excessive concentration of hydrogen chloride from accumulating in the reaction mixture. The resulting 4-chlorobutanal was heated in benzene containing excess ethylene glycol and some p-toluenesulfonic acid in a system equipped for azeotropic removal of water. Thus, from 200 g of 4-chlorobutyryl chloride there was obtained, after distillation through a 24" spinning band column, 145g (68%) of the chloroacetal, bp 91-92°C/18mmHg n25D 1.4512.

* J Gen Chem USSR 31, 1433 (1961)

JCS Perkin Trans 1, 253 (1981)

A stirred suspension of 5% Pd/BaSO4 catalyst (4 g) in toluene (500 ml, distilled from phosphorus pentoxide and stored over sodium) and 4-chlorobutyryl chloride (40 g) was heated under reflux while a 1:1 mixture of hydrogen and nitrogen was bubbled through the reaction mixture. When no more hydrogen chloride was evolved (ca 4-6 h) the mixture was cooled, filtered (Celite), treated with a solution of sulphuric acid (1 ml) in methanol (100 ml), and maintained at room temp for 30 min. The mixture was washed successively with saturated aqueous sodium hydrogen carbonate (200 mL), water (4x100 ml), saturated sodium chloride solution (200 ml), and then dried (Na2SO4).

Most of the toluene was removed by distillation (37x2 cm column) under reduced pressure (bp 51°C/100mmHg) and the residue distilled (10x1cm helices column) to give 4-chloro-1,1-dimethoxybutane  (22.7g, 53%), bp 76-78°C/20mmHg (lit. 84-85°C/25mmHg). Yields were not always reproducible; a rapid gas flow removed hydrogen chloride as it was produced and minimised polymerisation of the intermediate aldehyde.


A solution of freshly distilled 4-chloro-1-butanol (8 g, 73.7 mmol) in dry dichloromethane (20 ml) was added all at once to a suspension of pyridinium chlorochromate (23.8 g, 1.5 equiv) in dry dichloromethane (200 ml), and the resultant mixture was stirred for 3 hours at room temperature. It was then diluted with dry ether, filtered through a pad of celite and neutral alumina, the black gum being triturated in dry ether. The solution was concentrated to give 6.04 g (77%) of the title compound as a pale yellow fragrant liquid: IR (film): 2950, 2870, 2820, 2720, 1720 cm-1; 13C NMR (22.4 MHz): 6 200.7 (CHO), 43.9, 40.7, 24.8.

Reference: Tetrahedron 50, 11677 (1994)

4-Chloro-1,1-dimethoxybutane (4-chlorobutanal dimethyl acetal)
J. Chem. Soc. Perkin Trans. 1, 251 (1981)

We used a method based upon that of Pleshakov et al.[15] A stirred suspension of 5% palladium-barium sulphate catalyst (4 g) in toluene (500 ml, distilled from phosphorus pentoxide and stored over sodium) and 4-chlorobutyryl chloride (40 g) was heated under reflux while a 1 : 1 mixture of hydrogen and nitrogen was bubbled through the reaction mixture. When no more hydrogen chloride was evolved (ca. 4-6 h) the mixture was cooled, filtered (Celite), treated with a solution of sulphuric acid (1 ml) in methanol (100 ml), and maintained at room temperature for 0.5 h. The mixture was washed successively with saturated aqueous sodium hydrogen carbonate (200 ml), water (4x100 ml), saturated sodium chloride solution (200 ml), and then dried (Na2SO4). Most of the toluene was removed by distillation (37 x 2 cm column) under reduced pressure (bp 51°C/100mmHg) and the residue distilled (10-cm x 1-cm helices column) to give 4-chloro-1,1-dimethoxybutane (22.7 g, 53%), bp 76-78°C/20mmHg (lit.[16] 84-85°C/25mmHg). Yields were not always reproducible; a rapid gas flow removed hydrogen chloride as it was produced and minimised polymerisation of the intermediate aldehyde.

[1] JACS 95, 2656 (1973) [see below]
[15] J. Gen. Chem. USSR 31, 1433 (1961) as modified in [1].
[16] Tetrahedron 26, 3761 (1970)

JACS 95, 2656 (1973)

The Rosenmund reduction of 4-chlorobutyryl chloride was carried out as previously described [Ref 15 above]. A high flow rate (>200 ml/min) of hydrogen or of a mixture of hydrogen and nitrogen had to be maintained in order to prevent an excessive concentration of hydrogen chloride from accumulating in the reaction mixture. The resulting 4-chlorobutanal was heated in benzene containing excess ethylene glycol and some p-toluenesulfonic acid in a system equipped for azeotropic removal of water. Thus, from 200 g of 4-chlorobutyryl chloride there was obtained, after distillation through a 24-in. spinning band column, 145g (68%) of the chloroacetal, bp 91-92°C/8mmHg.


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Prep of 4-Chlorobutanol from THF/HCl(aq)
« Reply #16 on: August 19, 2003, 12:42:00 PM »
The refs found in

Post 317497

(3base: "THF --> 4-chloro-butan-1-ol", Novel Discourse)


Tetrahydrofuran (114 g, 1.58 mol) was heated to its boiling point and a slow stream of hydrochloric acid gas was bubbled into the liquid. After 8 h, the internal temperature of the reaction mixture had reached 100°C and the reaction mixture was allowed to cool. Excess THF was removed (rotary evaporator) and the residue was distilled under reduced pressure to give 88 g (45%) of 4-Chloro-1-butanol, bp 65-76°C/7mmHg [lit2 by 65-75°C/7mmHg].

1H NMR (CDCl3): 1.48-2.02 (m, 4 H, CH2), 3.20-3.82 (m, 4 H, CH2Cl and CH2OH), and 3.90 (s, 1 H, OH).
13C NMR (CDCl3): 29.22 (CH2, C-3), 29.94 (CH2, C-2), 45.00 (CH2Cl), 61.44 (CH2OH).

"Hydrolysis [of the dienol ether] in THF/HCl (5 M aqueous) at 100°C leads to the formation of the thermodynamic product, 2-cyclohexenone. However, our experiments showed that under these conditions THF is not very stable, and a significant amount of 4-chloro-n-butanol is formed as a result of THF reaction with HCl [...]"3

[1] C. N. Barry & S. A. Evans, J. Org. Chem. 46, 3361-3364 (1981)
[2] D. Starr & R. M. Hixon, Org. Synth. Coll. Vol. 2, p. 571 (1943)
[3] A. J. Pearson & A. V. Gontcharov, J. Org. Chem. 63, 152-162 (1998)


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Preparation of 4-halobutanal acetals
« Reply #17 on: December 11, 2003, 07:32:00 AM »
The following article retrieved and typed by Azole.

<Preparation of 4-halobutanal acetals.>, from
M. G. Pleshakov, A. E. Vasil'yev, I. K. Sarycheva, and N. A. Preobrazhenskii
Zhurnal Obshchei Khimii, 31(5), 1545-7 (1961).
C. A., 55, 23339 (1961)
Probably, J. Gen. Chem. USSR, 31, 1433 (1961) is the same article translated into English. I can only guess since I have no access to the English version of the journal.

2-(?-Chloropropyl)-1,3-dioxolane. A stream of hydrogen was passed into a refluxing mixture of ?-chlorobutyric acid chloroanhydride (35 g) [5], toluene (200 ml), and Pd/BaSO4 (3.5 g) [6] until hydrogen chloride evolution ceased [7]. The catalyst was separated and conc. H2SO4 (0.5 ml) and ethylene glycol (40 ml) were added to the filtrate with stirring at 18-20°. The resulting mixture was refluxed for 4 h [8]. After removal of the solvent, the residue was distilled. Yield 23.9 g (64.2%), b.p. 78-79° (10 mm Hg), d204 1.1520, n20D 1.4548 .

2-(?-Iodopropyl)-1,3-dioxolane. A mixture of 2-(?-chloropropyl)-1,3-dioxolane (30 g), acetone (200 ml) and sodium iodide (45 g) was refluxed for 12 h. Then the reaction mixture was cooled to 18-20° and the precipitate was separated. After removal of the solvent, the residue was distilled. Yield 29.9 g (62.1%), b.p. 69-70° (0.6 mm Hg),  d204 1.6971, n20D 1.5248 .

   5. W. J. Close, J. Amer. Chem. Soc., 79, 1455 (1957).
   6. E. Mosettig, R. Mozingo, in: Org. React., vol. IV, p. 368.  Originally, the authors refer to the Russian translation of this series, the page number was given for the experimental part.

Patent GB700825

   8. S. S. Nigam, B. C. L. Weedon, J. Chem. Soc., 1956, 4049.


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Fisher w/ AcOH
« Reply #18 on: January 07, 2004, 07:25:00 PM »
Here is a great paper originally suggested by Vaillo:

Post 456583

(Vaillo: "A new route to 4-(N,N-dimethylamino)butanal", Tryptamine Chemistry)

The Fisher synthesis for 5-alkoxy tryptamines (5-MeO-DMT) is suggested to only give good results with aq. AcOH as a catalyst. The paper also containes other valuable information related to this indole synthesis.

Indole Compounds. III.* The Direct Indolization to 5-Methoxy- and 5-Benzyloxy-N,N-Disubsfiluted Tryptamines

Croatica Chemica Acta, 36, 103-109 (1964)


Experimental for indolization:

Preparation of 5-methoxy- and 5-benzylioxy-N,N-disubstituted triptamines
The reaction was carried out on a 2.5-5 mmole scale with equimolar amounts of the reactants. The condensation was performed in a three-necked flask fitted with a mechanical stirrer a condenser and a dropping funnel.

Procedure A. 5-Methoxy- or 5-beazyloxy-phenylhydrazine hydrochlorlde was dissolved in 25% acetic acid (15-25 ml) at 80° and under stirring the corresponding N,N-disubstituted 4-aminobutanal diethyl acetal was dropped in during 5 minutes. The stirring and heating was continued for 2.5 hours. If the reaction mixture was very dark, charcoal (0.10-0.15 g.) Was added to the warm solution. After filtration the filtrate was evaporated in vacuo to dryness.

Procedure B, was identical with A. except that after the addition of acetal, concentrated hydrochloric acid (2 moles per 1 mole of hydrazine) was added to the reaction mixture.

Thanx to Rhodium for hosting the paper and for the tipps.


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Tryptamines from Halogenocarbonyl Compounds
« Reply #19 on: May 21, 2004, 08:03:00 AM »
Tryptamines and Related Structures From ?- and ?-Halogenocarbonyl Compounds and Arylhydrazines
Grandberg, I. I.

Zhurnal Organicheskoi Khimii, Vol. 19, No. 11, pp. 2439-2452 (1983) [Engl. Transl.]


A considerable range of papers on the synthesis of biogenic amines of the indole series and related structures from aryl- and heteroarylhydrazines and ?- or ?-halogenocarbonyl compounds are discussed systematically in the article. The reaction mechanism is investigated in detail by the isolation of all the intermediate products, the data from isotopic analysis, and kinetic measurements. The generality of the approach made it possible to assign these reactions to the special case of the well-known Fischer synthesis of indoles and at the same time to solve the problem of the principal stage of this synthesis (formation of the C-C bond), which it is proposed to treat as a sigmatropic [3,3]-rearrangement.
____ ___ __ _

The following article is an older one by the same author on this topic. Originally posted in

Post 436354

(Rhodium: "Archive of  "Wanted References" Volume 1", Novel Discourse)

Indolylalkylamines From Arylhydrazines and gamma- and delta-Halocarbonyl Compounds (Review)
Grandberg, I. I.

Chem. Heterocycl. Compd. (engl. Transl.) 10, 501 (1974)

____ ___ __ _

This article also features a preparation of 4-chlorobutanal from 4-chlorobutyryl chloride in 92% yield, using Rosenmund Reduction conditions.

Analogues of Psilocin and Lysergic Acid Diethylamide. I.  Chloro, Nitro, and Amino Derivatives of 3-Substituted Indoles
J. B. Mckay, R. M. Parkhurst, R. M. Silverstein, and W. A. Skinner

Canadian Journal of Chemistry 41, 2585-2590 (1963)


A number of indole derivatives structurally related to either psilocin or lysergic acid diethylamide (LSD) were synthesized. The following structural analogues of psilocin are reported: 4-chloro-3-dimethylaminoethylindole, 4-nitro-3-dimethylaminoethylindole, 4-nitro-3-aminoethylindole, 4-amino-3-dimethylaminoethylindole, and 4-amino-3-aminoethylindole. Compounds structurally related to LSD that were synthesized are: 3-(?-carboxyethylaminoethyl]-4-nitroindole and 4-nitro-3-[N-methyl-N-(N',N'-diethylcarboxamidoethyl)-aminoethyl]indole. Several 3,5- and 3,6-disubstituted indoles are also reported.


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4-Aminobutanal Acetals + 5-MeO-Tryptamine
« Reply #20 on: May 21, 2004, 07:05:00 PM »
More by the same author as in

Post 481048

(dioulasso: "Fisher w/ AcOH", Tryptamine Chemistry)

The Synthesis of 3,5-Disubstituted Indoles by Cyclization under Mild Conditions
D. Keglevic, N. Stojanac, and D. Desaty

Croatica Chemica Acta 33, 83-88 (1961)


3-Benzyloxy-6-formylaminotoluene (III) could not be converted by Madelung cyclization into the corresponding indole derivative. It was found, that 4-aminobutanal diethyl acetal and p-benzyloxyphenylhydrazine hydrochloride cyclize into 5-benzyloxytryptamine hydrochloride (V) in 25% acetic acid at 80°C in 68% yield. Under these mild conditions also other 3,5-substituted indoles were obtained: 3-methyl-5-benzyloxyindole (VI), 3-ethyl-5-benzyloxyindole (VII), 5-methoxytryptamine picrate (VIII) and N-acetyl-5-methoxytryptamine (Melatonin, IX).
____ ___ __ _

Aminoacetals. Syntheses of N,N-Disubstituted 4-Amino-2-butynal- and 4-Aminobutanal acetals
D. Keglevic and B. Leonhard

Croatica Chemica Acta 35, 175-180 (1963)


The synthesis of N,N-disubstituted 4-aminobutanal acetals (XV-XXII) was effected by the hydrogenation of the corresponding acetylenic analogues. N,N-Disubstituted 4-amino-2-butynal acetals (IV-XII) were prepared by the Mannich condensation of propargylaldehyde acetal, formaldehyde and the corresponding secondary amine. As an alternative route to N,N-disubstituted acetylenic aminoacetals. Bodroux-Tschitschibabin acetal synthesis was also applied in the preparation of 4-dibenzylamino-2-butynal acetal (VII).


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4-Dialkylaminobutyraldehyde acetals
« Reply #21 on: July 11, 2004, 10:05:00 AM »

Patent WO03101931

Abstract: The invention disclosed in this application relates to an improved process for the preparation of compounds of formula (I): R1R2NCH2CH2CH2CH(OR3)2; wherein, R1 = R2 = C1-C16 alkyl; C3-C7 cycloalkyl; R1 = C1-C16 alkyl; R2 = C3-C7 cycloalkyl; NR1R2 = pyrrolidino, piperidino, morpholino, thiomorpholino, R1 = C1-C6 alkyl; R2 = ArCH2; Ar =4-R4-C6H4-, R4 = MeO, EtO, Me, Et, NMe2, NEt2, SMe, SEt, etc; R3=C1-C6 alkyl; C3-C7 cycloalkyl which comprises: (i) Reacting 3-(N, N-disubstitutedamino)propyl halide of formula (XXI): R1R2NCH2CH2CH2X; wherein, R1, R2 = as defined above, X = Cl or Br, with magnesium in the presence of a solvent to get the Grignard reagent 3-(N, N-disubstitutedamino)-propylmagnesium halide; (ii) Reacting the resulting 3-(N, N-disubstitutedamino) propylmagnesium halide (Grignard reagent) with the trisubstituted orthoformate of formula (XVII): HC(OR5)(OR3)2; wherein, R3 and R5 is same or different and represent C1 to C6 alkyl, C3 to C7 cycloalkyl OR R3 is as defined above and R5 represents phenyl radical; (iii) Filtering off the resultant reaction mixture and distilling the filtrate to isolate the compound of the formula (I). These substituted butyraldehyde derivatives of the formula (I) are very important building blocks for the synthesis of various tryptamine derivatives. In particular 4-(N, N-dimethylamino)butyraldehyde dimethyl or diethyl acetals are crucial intermediates for the synthesis of commercially available anti-migraine drugs, like sumatriptan, zolmitriptan, and rizatriptan.


N-(3-chloropropyl)-N,N-dimethylammoniumchloride ("C(CC[NH+](C)C)Cl")


triethylorthoformat ("C(OCC)(OCC)OCC")

Both compounds are commercially available and cheap.


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R2N(CH2)3MgCl + HC(OEt)3 : previous work
« Reply #22 on: September 22, 2004, 07:27:00 AM »
The following article was requested by Lego:

Oximes of ?-Dimethylaminoalkanals and derivatives thereof
I. N. Somin, S. G. Kuznetsov
Zh. Org. Khim.
, 1(11), 1973-1976 (1965).
(journal written in Russian)

   For the preparation of the oximes (Table 1), diethyl acetals of the corresponding aminoaldehydes were subjected to hydrolysis. The aminoaldehydes formed are unstable and polymerize readily [2,3], so we converted them to oximes without isolation.
?-Dimethylaminobutyraldehyde diethylacetal was obtained from 3-dimethylaminopropylmagnesium chloride and orthoformic ester in 30% yield following the procedure described for the analogous dibutylamino derivative [5], b. p. 73-75° (6 mm), n20D 1.4217. Literature data [2]: b. p. 94-95° (11 mm), n20.5D 1.4227.

[2] V. Harries, F. Düvel, Liebigs Ann. Chem., 410, 54 (1915).

[3] R. Voet, Bull. Soc. Chim. France, 45, 61 (1929);
    F. E. King, J. R. Marshall, P. Smith, J. Chem. Soc., 1951, 239. 

[5] is the article below:

Attempts to Find New Antimalarials. Phenanthryl- and Quinolyl-alkamines of the Type RCHOH(CH2)3-11N(C4H9)2
T. D. Perrine
J. Org. Chem.
, 18, 1356-1367 (1953).

   The best approach found for the synthesis of ?-dibutylaminobutyraldehyde... involved the reaction of IV (Bu2N(CH2)3MgCl) with ethyl orthoformate [4] which yielded the diethyl acetal of ?-dibutylaminobutyraldehyde in about 60% yield. Mild acid hydrolysis afforded the free aldehyde in 86% yield. It is remarkably stable and can be distilled at atmospheric pressure.
   3-Dibutylamino-1-chloropropane was prepared as described by Marxer [2].
   Grignard reagents from dibutylamino halides. By observing certain precautions, the above halides may easily be converted to Grignard reagents. The chief factors affecting the conversion can be enumerated as follows:

   1. Moisture must be rigorously excluded. We used an apparatus in which ether from ethereal methylmagnesium iodide was directly distilled into the reaction flask. This ether was used both to help in drying the apparatus, and as a reaction solvent.

   2. The magnesium should be activated with methyl iodide or ethyl bromide. We used a reaction flask with a stopcock sealed to the bottom for removing the activating solution  prior to the introduction of the amino chloride.

   3. The minimal amount of ether should be used in the initial phase of the reaction.

   4. Stirring should be employed sparingly, if at all, until the reaction is well under way.

   5. Once started, the reaction should be continued unabated until complete.

   After activating the magnesium (a large excess is advantageous) with about 5 ml. of methyl iodide, employing vigorous stirring, and removal of the activating solution, a small amount of ether was distilled into the reaction flask and about 5 ml. of the amino halide added. The reaction usually started promptly, warming being rarely necessary. The reaction was kept going steadily by the addition of the amino chloride, diluted if desired with one or two volumes of ordinary anhydrous ether. The desired concentration was maintained in the reaction flask by distilling in ether from the methylmagnesium iodide flask. Moderate stirring was usually employed. The reaction was completed by heating at reflux for 0.5 hour. The yields were usually 80-85%.

   These Grignard reagents are fairly insoluble in ether, and crystallize either at once, or on long standing. They are easily soluble in benzene. A normal color test (Gilman's color test I) is obtained with Michler's ketone and iodine in acetic acid. We were unable to prepare the Grignard reagents in which the halogen and nitrogen atoms were separated by 4 and 5 carbon atoms respectively.

   ?-Dibutylaminobutyraldehyde*. Ethyl orthoformate (100 g.) and 320 ml. of 0.85 N 3-dibutylaminopropylmagnesium chloride in benzene were kept at 65° for 15 hours to give 47 g. (60%) of ?-dibutylaminobutyraldehyde diethylacetal, b. p. 90-110°/2 mm., and on redistillation, b. p. 149.5°/9 mm., n29D 1.4330.
   On mild acid hydrolysis this gave the aldehyde (86% yield) of b. p. 235°; 71.0°/0.08 mm., n30D 1.4398 (1.4460 after 16 hours).
   The 2,4-dinitrophenylhydrazone melted at 65-67°.

   *The Stephen reaction [13] on ?-dibutylaminobutyronitrile gave none of this aldehyde; ?-chlorobutyronitrile (6.6 g.), 17 g. of anhydrous SnCl2, and 80 ml. of dry ether gave, after 18 hours at 0°, a 10% yield of ?-chlorobutyraldehyde as the 2,4-dinitrophenylhydrazone, m. p. 132° (from alcohol).

[2] Marxer, Helv. Chim. Acta, 24, 209E (1941).

[4] Smith and Bayliss, J. Org. Chem., 6, 437 (1941).

[13] Stephen, J. Chem. Soc., 127, 1875 (1925).

As I can see, these articles are not mentioned in the patent posted by Lego  :)