4 more ways to make mescaline (rough draft).

[cattleprodder]

This, being a rough draft, does not contain all the reaction specifics so you'll have to pardon my lack of detailed information at the present time.  They (the reaction specifics that is) should not be all that hard to look up by any number of persons, however.

(1)  Hydroboration, Jones' Reagent Oxidation, Hunsdiecker reaction, Sn2 displacement with NH3 or NaN3 (sodium azide) followed by reduction with LiAlH4 in ether. 

Elemicin + diborane (3HB-BH3) + THF --> H2O2 + OH- --> CrO3 +H2SO4 in acetone --> 3,4,5-trimethoxyphenylpropionic acid + Ag2O or mercury or lead salts -->  silver (or mercury or lead)...propionate + Br2 -->  3,4,5-trimethoxyphenylethylbromide + AgBr + CO2

3,4,5...bromide in DMF or DMSO or ACN + NaN3 followed by reduction with LAH --> mescaline

Anhydrous ammonia may be used in the place of sodium azide since the bromine is attached to a primary carbon and, in that case, no reduction with LAH would be necessary.
 
(2) Wacker oxidation, Haloform reaction, R-CO2H reduction, PBr3 bromination, Sn2 nucleophilic amination. 

Elemcin + benzoquinone + PdCl2 + O2(g) --> 3,4,5...phenylacetone + I2 or Br2 + OH- -->  3,4,5...phenylacetic acid + CHI3 or CHBr3

3,4,5...acid + B2H6 in THF or diglyme (very radid rxn., works at room temp.)--> 3,4,5...phenylethyl alcohol + red P + Br2 --> 3,4,5...bromide + anhydrous NH3 in ACN, DMF or DMSO or 3,4,5...bromide + sodium azide followed by LAH reduction --> mescaline

(3) KMnO4 vigorous benzylic oxidation of elemicin, reduction with diborane in diglyme or THF, PBr3 bromination, KCN nucleophilic displacement of bromide ion, reduction with LAH in dry ether --> mescaline.

With this one, alpha, beta-quatrodeuteromescaline are made possible.  See under beta-D in PIHKAL and then use LiAlD4.

(4) Hofmann Rearrangement

Convert elemicin to its propionate form (see above), acylization with SOCl2, amide formation with ammonia, Hofmann degradation with Br2 and OH- --> mescaline. 

Mescaline is my favorite drug in the world so far, followed in no particular order by MDA, MDE, kind bud, ETH-LAD and psilocybin. 

Gotta go...

[Vitus_Verdegast]

If you want to work with elemicin, the trimethoxyphenylacetaldehyde can be obtained by ozonolysis, this is then transformed to the oxime and finally reduced.

refs for this rxn are : Hahn and Wassmuth, Chem. Ber. 67, 1934, p.696 and Hahn, Chem. Ber. 67, 1934, p.1210.



 ArCHO + CH₂(COOH)₂  ^__>  ArCH=CHCOOH  ^__>  ArCH₂CH₂COOH  ^__>  ArCH₂CH₂CONH₂  ^__>  ArCH₂CH₂NH₂

refs for this (using 3,4,5-TMB) are : Slotta, K.H., J. Prakt. Chem. 133, 1932, 129 and Slotta and Heller, Chem. Ber. 63, 1930, 3029.
Also: Kulkarni et al., Indian J. Chem., 5, 1967, 471 ; Schwachhofer and Chaplin, Bull. Soc. Chim. Fr., 1962, 835 ; McCarty et al., J. Med. Chem., 11, 1968, 534 and Habermehl and Khalique, Pak. J. Biol. Agr. Sci. 10, 1967, 46.

The propionamide could also be prepared by oxidation of the phenylacetonitrile with H₂O₂ in alkaline EtOH (the Swachhofer ref).


ArCOCH₃  ^__>  ArCH₂COOH  ^__>  ArCH₂CONH₂ + LiAlH₄  ^__>  ArCH₂CH₂NH₂

refs are  : Beasley and Burger, J. Med. Chem. 7, 1964, 686 and Benington et al, J. Org. Chem., 22, 1957, 332.


ArCHO  ^__>  ArCH(OH)CN  ^__>  ArCH(OAc)CN  ^__>  ArCH₂CH₂NH₂

refs are : Kindler and Peschke, Arch. Pharm., 270, 1932, 410 and Amos, Aust. J. Pharm., 45, 1964, S8.


Saved the best for the last :

1-bromo-2-phtalimidoethane  +  2,6-dimethoxyphenol  +  AlCl₃  ^__>  3,5-dimethoxy-4-hydroxy-beta-phenylphtalimidoethane  ^__Me₂SO₄^__>  3,4,5-trimethoxy-beta-phenylphtalimidoethane  ^__H^+__> mescaline

The name of the journal is almost as funky as this rxn  : Rabusic and Gregor, Spisy Prirodoved. Fak. Univ. Brne, 480, 1967, 85  (Chem. Abstr. 68:86944, 1968).

[ChemisTris]

Aminoalkylation of phenol ethers.  I.     Rabusic, Emil; Gregor, Miroslav.    Univ. J. E. Purkyne,  Brno,  Czech.   Spisy Prirodovedecke Fakulty University v Brne (1967),  No. 480  85-92.  Journal  written in Czech.

Abstract:
Aminoalkylation of phenol ethers with w-phthalimidoethyl bromide (I) was studied under Friedel-Crafts reaction conditions.
Thus, to a solution of 5.1 g w-phthalimidoethyl bromide and 3.1 g 2,6-dimethoxyphenol in 500mL Et₂O was added in portions 2.66 g anhydrous AlCl₃, and the mixture kept at room temp., heated 2 hours at 60°, and worked up to a yield 25% alpha-phthalimido-beta-3,5-dimethoxy-4-hydroxyphenyl)ethane (II), mp 81° (H₂O). To an Et₂O solution of CH₂N₂ from 8.0 g H₂NCON(NO)Me was added in portions 4 g II and the Et₂O layer worked up to yield approx. 100% alpha-phthalimido-beta-(3,4,5-trimethoxyphenyl)ethane (III), mp 72° (Et₂O).
III (2.0 g) and 20 mL aqueous HCL was heated 4 hours, cooled, pptd. phthalic acid filtered off, and the filtrate evapd., to give 30% beta-(3,4,5-trimethoxyphenyl)ethylamine-HCL (IV), mp 178-80° (H₂O).

Similarly as for II was prepd. from 5.1 g I, 2.58 g pyrogallol, and 2.66 g AlCl₃ in 300 mL Et₂O, 75.7% alpha-phthalimido-beta-(2,3,4-trihydroxyphenyl)ethane (V), mp 85°, 4 g of which and the Et₂O solution of CH₂N₂ from 24.0 g H₂NCON(NO)Me gave approx 100% alpha-phthalimido-beta-(2,3,4-trimethoxyphenyl)ethane, mp 78° which was converted by boiling with HCl to beta-(2,3,4-trimethoxyphenyl)ethylamine-HCl, mp 174-5° (H₂O) in 30% yield

[Antoncho]

Here are two procedures for making that b-bromoethylphthalimide used for FC aminoalkylations posted above.


1) From phthalic anhydride and ethanolamine/PBr₃

http://orgsyn.org/orgsyn/prep.asp?prep=cv4p0106

In a 1-l. round-bottomed flask are placed 74 g. (0.5 mole) of phthalic anhydride and 30 ml. (0.5 mole) of freshly distilled monoethanolamine. The mixture is heated on a steam bath for 30 minutes; the initial reaction is vigorous (Note 1). The reaction mixture is cooled to room temperature, and a reflux condenser is attached to the flask. To the cooled reaction mixture is added slowly, with shaking, 32 ml. (91.3 g., 0.34 mole) of freshly distilled phosphorus tribromide. The reaction flask is then placed on a steam bath and heated under reflux with occasional shaking for 1.25 hours (Note 2). The hot liquid reaction mixture is poured with stirring onto 750 g. of crushed ice. When the ice has melted completely, the crude ¦Â-bromoethylphthalimide is collected on a B¨¹chner funnel, washed with cold water, and allowed to dry for a few minutes. The crude product (Note 3) is dissolved in 1.2 l. of aqueous ethanol (50% by volume) with the aid of heat. If necessary a small amount of 95% ethanol is added to effect complete solution. The hot solution is filtered and cooled in a refrigerator. A white crystalline product weighing 94¨C99 g. is obtained. Concentration of the mother liquor to 400 ml. yields an additional 1¨C3 g. of product. The total yield of product is 95¨C102 g. (75¨C80%); m.p. 80¨C82¡ã.





2) From K-phthalimide and dibromoethane.

http://orgsyn.org/orgsyn/prep.asp?prep=cv1p0119

In a 1-l. two-necked round-bottomed flask fitted with an efficient stirrer and a reflux condenser are placed 150 g. (0.81 mole) of potassium phthalimide and 450 g. (2.4 moles) of ethylene dibromide (Note 5). The stirrer is started and the mixture is heated for about twelve hours in an oil bath maintained at 180¨C190¡ã. The condenser is then set for distillation, and the excess of ethylene dibromide is distilled under reduced pressure. The recovery of the bromide amounts to 290¨C295 g.






As a side note, .... It is obvious that the low yield in the 1st amino alkylation is due to the low reactivity of the starting phenol, not to its sensitivity..... Bad news.....(that is, we can't use fully methylated precursors).


But, for Gawd's sake, is it possible to use something other than diazomethane for methylation???  What, do we make a quat out of that imide in any other way?? Highly unlikely - that nitrogen should bee a bitch to methylate!

What do you think?




Antoncho

[Rhodium]

Good post, Antoncho, but note that dibromoethane is highly reactive/poisonus/carcinogenic, so please use the first method if possible.

[Vitus_Verdegast]

Why CH2N2?

Diazomethane is a powerful methylating agent for acidic compounds. Could it be that the phtalimido-group hydrolyses under basic conditions? If not, maybe they used it just because it was at hand?

I'll include this for information purposes only, only to be used by *professional chemists*, with a *professional lab*, *with a professional fume hood* and experienced technique :

(From the Merck Index)

Preparation of gaseous diazomethane from CHCl₃, hydrazine and KOH :
Ber., 45, 501 (1912)

J. Org. Chem., 33 4272 (1968)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/hydrazine2diazomethane.pdf)

Properties:  Very toxic yellow gas.  Explosive!  Use safety screen.  Insidious poison, a well-ventilated hood is absolutely necessary, avoid vapor.  mp -145°; bp -23°.  Undil liq and concd solns may explode violently, especially if impurities are present.  Gaseous diazomethane may explode on heating to 100° or on rough glass surfaces.  Ground glass apparatus and glass stirrers with glass sleeve bearings where grinding may occur, should not be used.  Alkali metals also produce explosions with diazomethane.  Sol in ether, dioxane.  Such solns dec only slowly at low temps.  Decompn is more rapid if alcohols or water are present.  Copper powder causes active decompn with the evolution of nitrogen and the formation of insol white flakes of polymethylene (CH2)x.  Solid calcium chloride or boiling stones have the same effect.  This phenomenon appears to occur always during the action of diazomethane on solid substances.
CAUTION:  Potential symptoms of overexposure are eye irritation; coughing, shortness of breath; headache; fatigue, flushing of skin, fever; chest pain, pulmonary edema, pneumonitis; asthma; direct contact with liquid may cause frostbite. 

[ylid]

How about this 2-stepper using the Willgerodt reaction? For those willing to risk death by H2S poisoning, that is:

  1. Elemicin straight to substituted 3-phenylpropionamide by treatment with ammonium polysulfide at 200-210°C^a
  2. Amide to phenethylamine by Hofmann degradation with alkaline hypochlorite<sup>b

  a</sup> King JA, McMillan FH. J. Amer. Chem. Soc. (1946) 68:632-635.
  Allylbenzene (3 cc.) and ammonium polysulfide (15 g.) were heated five hours at 200-210°C. The crystalline solid (ca. 1.5 g., crude yield about 45%) was filtered from the reaction mixture and recrystallized from water to give colorless crystals of p-phenylpropionamide, m. p. and mixed m. p. 100-101°C.
  ^b Weerman, Jongkees. Recl.Trav.Chim.Pays-Bas. (1906) 25:243.

Not wishing a smelly demise on myself, I have been considering a different route:

  1. Elemicin to 3,4,5-trimethoxy-benzaldehyde by one of the established methods
  2. Condensation with acetonitrile forming the substituted cinnamonitrile^c
  3. Reduction to the phenylpropionitrile^d,e
  4. Conversion to phenylpropionamide by treatment with concentrated hydrochloric acid at 40°C^f,g
  5. Hofmann degradation as previously<sup>h,i

  c</sup>

Post 424519

(ylid: "2CB via the cinnamonitrile", Methods Discourse)
  ^d NaBH4 in ethanol: Eckert, Heiner, Kiesel, Yvonne. Angew.Chem. (1981) 93:477-479.
  ^e Mg in methanol: Profitt et al. J.Org.Chem. (1975) 40:127-128.
  ^f Cordier. C.R.Hebd.Seances Acad.Sci. (1945) 220:177.
  ^g Vogel 3rd ed. p762
  ^h Weerman, Jongkees. Recl.Trav.Chim.Pays-Bas. (1906) 25:243.
  ⁱ Vogel 3rd ed. p413

[ylid]

I need to clarify a couple of things about that last post.

The first is that the reagent mentioned in the Willgerodt reference is 'yellow ammonium polysulfide' which I take to be the aqueous solution made by bubbling H2S through ammonia solution. Although presumably it doesn't stay aqueous at 200°C (?). According to Vogel p923-5 the addition of 40% dioxane or pyridine increases the mutual solubility of the reagents enabling a reduction of the reaction temperature to 160°C.


The second is that this method is lethally dangerous. I invite the thread moderator to comment on the safety of the procedure for backstreet chemists. In my opinion, the more people attempt it the more people will die. It’s that simple. If I can’t persuade you, then maybe Argox can. This is taken from Rodium’s page:

  I really want to stress that the novice clandestine chemist should never attempt to generate H2S. H2S is a deadly poison. There is no antidote. With a lethal dose measured in small ppm's, death can be expected in 15 minutes from acute cellular asphyxiation.
  I was once gassed with hydrogen cyanide, which is similar in toxicity to hydrogen sulfide, luckily there IS an antidote for cyanide poisoning, and my lab was equipped with a Lilly kit and my co-workers were quick to respond, and the chief chemist had the brains to show up at the emergency room in that poor South American town with a bottle of thiosulfate. Had the gas been H2S instead of HCN, Argox would not be here to tell the tale…
  I repeat that H2S is deadly poison, and if anything goes wrong, you and everybody in the immediate area will be at risk of dying. The obnoxious smell of H2S at low concentrations quickly overwhelms the senses at higher concentrations, and it is quite common for the victim to assume that 'the smell went away, so everything's OK.' Usually the last wrong assumption they ever make.

  The Kindler variation of the Willgerodt procedure uses elemental sulfur and morpholine to achieve similar ends, but from what information I can gather (not having any chem experience or training) H2S tends to be released all the same. In particular H2S is evolved if the phenylthio-propiomorpholide is hydrolysed with aqueous acid. Hydrolysis with KOH may be a safer alternative

Post 305146

(Rhodium: "Basic hydrolysis of the willgerodt intermediate", Novel Discourse)

[ylid]

This is to carry out the final step of the above reaction scheme without using Br2 / NaOH.

The Hofmann Rearrangement Using Household Bleach: Synthesis of 3-Nitroaniline
Keith A. Monk and Ram S. Mohan, J. Chem. Ed. (1999) 76:1717

Introduction
The Hofmann rearrangement involves the conversion of an amide to an amine containing one fewer carbon atoms, by treatment with bromine (or chlorine) and alkali ¹. The mechanism of this reaction is discussed in detail in most sophomore organic chemistry text books. Yet very few examples of this rearrangement are found in lab texts ². With aromatic amides containing an electron-withdrawing group, hydrolysis to the corresponding carboxylic acid under the basic reaction conditions is often a serious competing side reaction. It has been reported that at elevated temperatures, the rearrangement is much more rapid than hydrolysis ³. We have successfully carried out the rearrangement of 3-nitrobenzamide at 80°C using household bleach.¹ This procedure avoids the use of bromine and sodium hydroxide, which is typically used to effect the Hofmann rearrangement. The preparation of 3-nitrobenzamide from benzamide has been previously reported as a laboratory experiment ⁴. These two reactions can be completed in two-and-a-half hours, making this sequence a new and useful addition to the list of organic chemistry laboratory experiments.

Experimental Procedure
  ...The concentration of household bleach solution was determined to be 5.25% (wt/wt) by iodometric titration. Finely powdered 3-nitrobenzamide (1.5 g, 9.03 mmol) was added to a 125-mL Erlenmeyer flask containing a magnetic stir bar, 18 mL of 1 M NaOH (18 mmol), and 13.3 mL (14.1 g) of household bleach (9.93 mmol).2 The well-stirred mixture was heated at 80 °C in a water bath for 30 min. The mixture was cooled to 50 °C and then 10% aqueous NaHSO3 (10 mL) was added, which resulted in the precipitation of a yellow solid. The flask was cooled in an ice bath and the solid was collected by suction filtration. Recrystallization from 95% ethanol gave 1.01 g (80%) of silky yellow crystals. The product was identical by TLC, mp, 1H NMR, and 13C NMR with an authentic sample of 3-nitroaniline.

CAUTION: Nitro compounds are often toxic. Gloves should be worn throughout this experiment. Contact should be avoided with bleach solutions.

Notes
  1. It has been reported that 2-nitroaniline, the product of Hofmann rearrangement of 2-nitrobenzamide, reacts with NaOCl and alkali to give benzofuroxan ⁵. Under the same conditions 4-nitrobenzamide gives 50% 4-nitroaniline and 50% 4-nitrobenzoic acid ³.
  2. The presence of excess bleach is checked using starch–iodide paper.

Literature Cited
  ¹ For a review see Organic Reactions, Vol. III; Adams, R.; Bachman, W. E.; Fieser, L. F.; Johnson, J. R.; Snyder, H. R., Eds.; Wiley: New York, 1947; p 247.
  ² For an example, see Campbell, B. N.; Ali, M. M. Organic Chemistry Experiments. Microscale and Semi-Microscale; Brooks/Cole: Pacific Grove, CA, 1994. Schreck, J. O. J. Chem. Educ. 1968, 10, 670.
  ³ Hauser, C. R.; Renfrow, W. B. J. Am. Chem. Soc. 1937, 59, 121.
  ⁴ McElveen, S. R.; Gavardinas, K.; Stamberger, J. A.; Mohan, R. S. J. Chem. Educ. 1999, 76, 535.
  ⁵ Green, A. G; Rowe, F. M. J. Chem. Soc. 1912, 101, 2443.

http://jchemed.chem.wisc.edu/Journal/Issues/1999/Dec/PlusSub/V76N12/p1717.pdf

[ylid]

Vanillin can be prepared from eugenol, and iodinated on the way to mescaline:

https://www.thevespiary.org/rhodium/Rhodium/chemistry/iodovanillin.html

. But homovanillin can be prepared from eugenol without first isomerizing the allyl side chain, and has the right number of carbons on the side chain for a phenylethylamine. With eugenol as the starting material, it seems like it could be worth trying to adapt the iodination/methylenation procedure substituting homovanillin for vanillin. The acetaldehyde can then be worked up into the phenethylamine by the Leuckart reaction, or via the oxime as below. Sodium amalgam can also be used to reduce the oxime:

https://www.thevespiary.org/rhodium/Rhodium/chemistry/mescaline.alkaloids.html

1. homovanillin (3-methoxy-4-hydroxy-phenyl-acetaldehyde) by ozonolysis of eugenol
 

Post 428394 (missing)

(ylid: "Reduction of allylbenzene ozonide using Zn/AcOH", Novel Discourse)

2. 5-hydroxy-homovanillin
 

https://www.thevespiary.org/rhodium/Rhodium/chemistry/iodovanillin.html

3. 3,4,5-trimethoxy-phenyl-acetaldehyde
 

https://www.thevespiary.org/rhodium/Rhodium/chemistry/betaine.html

4. mescaline

beta-(Hydroxyphenyl)ethylamines and their transformations. II. Synthesis of further amines and of the corresponding (hydroxyphenyl) acetic acids from natural allyl compounds.
Hahn G, Schales O (1934) Ber.  1486-93

  cf. C. A. 28, 4047.3.  The method of obtaining beta-(hydroxyphenyl)ethylamines and the corresponding acetic acids from allyl compounds has been applied to other natural products and further improved.  The allyl compounds, after ozonization (1% O₃ again gave the best results), were converted directly into the oximes without isolating intermediate products, and the oximes changed into the nitriles by boiling with Ac₂O, and finally the nitriles were, rapidly reduced, catalytically, to the amines by slowly dropping them in AcOH into a suspension of the catalyst in AcOH-H₂SO4.  On the other hand, saponification of the nitriles gave the acids almost quantitatively.

  Safrole, methyleugenol, eugenol and myristicin gave, respectively, homopiperonal oxime, mp 115°C (79% yield), homoveratraldoxime, mp 91°C (71%), homovanillin oxime, mp 115°C (63%), and homomyristicylaldoxime, mp 80°C (34%).  These in turn yielded 3,4-methylenedioxybenzyl cyanide, bp14 164-6°C, mp 42°C (80%), 3,4-dimethoxybenzyl cyanide, bp20 184°C, mp 68°C (79%), 4-acetylhomovanillonitrile, bp16 204°C, mp 52°C (81%), and 3,4-methylenedioxy-5-methoxybenzyl cyanide, bp20 198°C, mp 90°C (80%).  From the nitriles were obtained homopiperonylamine bp18 146-8°C (93%), homoveratrylamine, bp14 156°C (90%), and homomyristicylamine, bp16 178°C (92%).  The nitriles also yielded on saponification, homopiperonylic acid, mp 128°C (96%), homoveratric acid, mp 98°C (97%), homovanillic acid, mp 143°C (92%), and homomyristicinic acid, mp 108°C (Kindler and Peschke, C. A. 26, 4590, give 127°C) (quantitative yield).

That 'homomyristicylamine' sounds like it might be worth a taste, too.

[ylid]

An alternative route from eugenol would be to work up elemicin the Indian way:

Post 381882

(GC_MS: "Eugenol -> elemicin and myristicin", Novel Discourse). The acetaldehyde can then be prepared as below before conversion to the phenethylamine.

Synthesis of 3,4,5-trimethoxyphenylacetaldehyde.
Duff JG, Pepper JM. (1956) Can. J. Chem. 34, 842-4.

Two synthetic routes were followed for the preparation of 3,4,5-(MeO) ₃C₆H₂CH₂CHO (3,4,5-trimethoxyphenylacetaldehyde; I).  3,4,5-(MeO)₃C₆H₂CH₂CH=CH₂ (elemicin, 20.8g) in 300ml 2:1 EtOH-H₂O was treated with 5.5g KMnO₄ in 1100ml H₂O at 15°C, and after 3 minutes the solution filtered, concentrated to 400ml, and extracted with benzene to give 12.2g 3,4,5-(MeO)₃C₆H₂CH₂CH(OH)CH₂OH (II), mp 83-4°C, which (6.4g) was oxidized with 3.7g HIO₄ in 500ml H₂O to 31% I, mp 39-40°C; semicarbazone, mp 186-7°C.  Oxidation of II with Pb(OAc)₄ gave 50.9% I.  3,4,5-(MeO)₃C₆H₂CHO (14.8g) with 9g ClCH₂CO₂Et in the presence of NaOEt formed a solid, which was hydrolyzed with warm aqueous HCl to 3.7% I.


This synth is an alternative to the ozonolysis method mentioned on Rhodium's page:

https://www.thevespiary.org/rhodium/Rhodium/chemistry/mescaline.alkaloids.html

beta-(Hydroxyphenyl)ethylamines and their transformations. I. Synthesis of mescaline.   
Hahn G, Wassmuth H (1934) Ber.  67B  696-708.

Ozonization of elemicin with 1% O₃ in AcOEt and subsequent hydrogenation of the ozonide with H and Pd-CaCO₃ gave 75% of 3,4,5-(MeO)₃C₆H₂CH₂-CHO as the NaHSO₃ compound, which yielded 72% of the oxime, mp 67°C (semicarbazone in. 191°C).  The oxime was converted by short boiling with Ac₂O into the nitrile, bp12 200-207°C, mp 81°C (80% yield), which, when dropped slowly into an AcOH-H₂SO₄ suspension of the Adams Pd sponge catalyst absorbed the calculated amount of H as fast as it was dropped in and gave 90-95% of I, mp 30-32°C, as the HCl salt, mp 178-180°C; picrate, mp 217-219°C.

[ylid]

It seems more trouble than a Henry reaction with MeNO₂ followed by reduction with Al/Hg, but just for the record:

  1. Condensation of 3,4,5-trimethoxybenzaldehyde with acetonitrile forming the substituted cinnamonitrile ^a
  2. Cinnamonitrile to cinnamamide ^b
  3. Cinnamamide to benzenepropanamide ^c,d
  4. Hofmann rearrangement to phenethylamine <sup>e

a</sup>

Post 424519

(ylid: "2CB via the cinnamonitrile", Methods Discourse)
 
^b Catalytic hydration of nitriles to amides with manganese dioxide on silica gel.
Liu KT, Shih MH, Huang HW, Hu CJ. Synthesis (1988) 9:715-17.

  Hydration of representative nitriles with silica gel-supported MnO₂ at the reflux temperature of hydrocarbon solvents gives the corresponding amides in good to excellent yield.  Phenylacetonitrile, however, was partially oxidized to benzoylformamide.  Other manganese catalyst systems were also evaluated. 

^c Selective reduction of alpha,beta-olefinic amides and lactams by magnesium and methanol.
Brettle R, Shibib SM. J. Chem. Soc. Perkin Trans. 1 (1981) 11:2912-19.
^d The selective reduction of alpha,beta-olefinic amides.
Brettle R, Shibib SM. Tet. Lett.  (1980) 21: 2915-16. 

  alpha,beta-Olefinic amides were reduced to the corresponding saturated amides by Mg and MeOH in good to high yield.

^e The Hofmann Rearrangement Using Household Bleach as above.