Ph-C---C + HMTA ---> Ph-CH-CH2-NH2
\ / |
O OH
Yield: 100% (cf. H J Roth, A Brandau. Arch Pharm 292 (1959) 761 (will be posted later ;) ).
3. Introduction of formyl groups: Sommelet reaction
Brevitate, the Sommelet reaction embraces three steps: (1) formation of a hexaminium salt, (2) hydrolosis of this salt at pH 2 and (3) reaction of the formed amine with an excess of HMTA to yield an aldehyde.
(1) HMTA + X-CH2-R --> HMTA(+)-CH2-R X(-)
(2) HMTA(+)-CH2-R X(-) --(H+)--> R-CH2-NH2 + HN=CH2
(3) R-CH2-NH2 + HN=CH2 --(H2O)--> R-CHO + NH3 + CH3-NH2
A couple of examples are given in the text and references therein.
4. Introduction of formyl groups: Duff reaction
The Duff reaction allows the synthesis of o-hydroxy aromatic aldehydes and shows some similarities with the previously mentioned Sommelet reaction. In the Duff reaction, phenols are reacted with hexamine in HBO2/dry glycerol or glacial acetic acid. In most cases, yields are rather low. A modification of the Duff formylation is the reaction of phenols with HMTA in trifluoroacetic acid (TFA). High p-selectivity is observed in this case.
benzene + HMTA/TFA (1:4 ratio) --> benzaldehyde (32% yield)
3,4-ethylenedioxybenzene + HMTA/TFA (1:1 ratio) --> 3,4-ethylenedioxybenzaldehyde (37% yield)
The procedure is written out in J Org Chem 37 (1972) 3972 (by W E Smith). I wonder what the yields would be if one tried 3,4-methylenedioxybenzene to obtain piperonal... Probably not tremendously high, but if conversion equals yield, recycling of the 3,4-methylenedioxybenzene is possible. The method seems rather OTC... (HMTA costs US$ 65.00 for 5 kg, according to the catalogues of one of my more expensive chem suppliers).
The text contains some more interesting chemistry, such as the synthesis of benzodiazepines using HMTA. If you think this article is interesting for your synthetic dreams, you (should) know where to get it!
Ph-CH---CH2 + HN---R --- 1 ---> Ph---CH---CH2---NR2
\ / | |
O R OH
--- 2 ---> Ph---CH---CH2---OH
|
NR2
We are interested to know if the aminolysis of styreneoxydes always yields two isomeres. We tested a large number of amines to form our conclusion:
1. NH3
2. primary amines: MeNH2, EtNH2, ethanolamine, gamma-methoxypropylamine, benzylamine, alfa-phenylethylamine, 1-phenyl-2-amine-ethanol, aniline, p-toluidine.
3. secondary amines: Me2NH, Et2NH, diethanolamine, pyrrolidine, piperidine, morpholine, piperazine, 1-ephedrine.
4. tertiary amines: Me3N, Et3N, triethanolamine, N-methylpyrrolidine, N-ethylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, N-methylmorpholine, N-ethylmorpholine, HMTA.
5. acidic amides: acetamide, benzamide.
6. N-substituted acidic amides: methylacetamide, ethylacetamide, methylbenzamide, ethylbenzamide.
7. dicarbonic acid imides: succinimide, phtalimide.
8. purine: theobromine, theophylline.
-R = Ph-CH-CH2-
|
OH
Am ratio St:Am solvent product yield
NH3 6:1 H2O/EtOH R-NH2 28.5%
also 7.3% of the isomere
NH3 3:1 " R-NH2 3.7%
also 11.2% R2NH and 59.5% R3N
MeNH2 1:3 H2O/MeOH R-NHMe 7.3%
MeNH2 2:1 " R-NHMe 82.0%
EtNH2 1:3 EtOH/H2O R-NHEt 36.0%
EtNH2 2:1 " R-NHEt 9.6%
also 78.5% R2-NHEt
Me2NH 1:1 EtOH R-NMe2 82.0%
Et2NH 1:1 EtOH R-NEt2 80.0%
HMTA 1:1 chloroform R-NH2 29.0%
also 0.54% of an intermediary product.
Reaction details not given; the text contains some further data on temperature and reaction times.
References:
2. M Tiffeneau, E Fourneau. C R 146 (1908) 697
3. W S Emerson. J Am Chem Soc 67 (1945) 516
4. W B Wheatley e.a. J Am Chem Soc 72 (1950) 1658
5. W Beck e.a. J Org Chem 16 (1951) 1434
6. C L Browne, R E Lutz. J Org Chem 17 (1952) 1187
7. J A Castro e.a. J Org Chem 19 (1954) 1444
Note: 1-phenyl-2-amino-1-ethanol. Waaw... must give you an enourmous psychedelic high... Obviously, SWiM is looking a bit further than that :P . Aminolysis of phenylpropenyl oxides? Styrene analogues that can be converted to PEAs?
R-CH--CH2 + HMTA + CHCl3 + 1/2 O2 --> RCH-CH2-NC6H12N3(+)Cl(-) + COCl2
\ / |
O OH
ethyleneoxyde HO-CH2-CH2-NH2
propyleneoxyde CH3-CHOH-CH2-NH2
styreneoxyde Ph-CHOH-CH2-NH2 (apophedrine)
beta-oxy-phenyl-ethyl-hexamethylenetetraminium chloride
10 g HMTA and 10 g styreneoxyde are dissolved in 150 mL chloroform and heated for 12 hours @ 40-50 C. After cooling down, 5.2 g needle-shaped crystals where obtained.
1-amino-2-phenyl-2-ethanol.H2SO4
4 g of the hexaminium chloride is dissolved in 10 mL EtOH with 10 mL 30% H2SO4 and heated in a water bath (10 minutes). The alcohol is removed via vacuum distillation and alkalified with NaOH. The water phase is extracted several times with ether. After removal of the ether, 1.3 g of a yellowish oil is obtained which easily forms crystals in alcoholic H2SO4. (the end product in this case is sometimes referred to as apophedrine).
There was a discussion not that long ago about converting ephedrine (and analogues) -> amphetamine (and analogues) with Pt or Pd... can't remember. Might work here as well, so you'd have a new route to PEAs in that case. There also has been a discussion about converting phenones to alkenes... Might be helpful in obtaining styrene analogues? ;)
Patent DE975297 (http://l2.espacenet.com/dips/viewer?PN=DE975297&CY=gb&LG=en&DB=EPD)
Post 381544 (https://www.thevespiary.org/talk/index.php?topic=7178.msg38154400#msg38154400)
(GC_MS: "Hexamethylenetetramine: a review", Chemistry Discourse)Synthesis, No. 3, pp. 161-176 (1979) (https://www.thevespiary.org/rhodium/Rhodium/pdf/hexamethylenetetramine.pdf)
(https://www.thevespiary.org/rhodium/Rhodium/pdf/hexamethylenetetramine.pdf)