(Hive Bee)
11-20-02 12:56
No 381544
      Hexamethylenetetramine: a review
(Rated as: excellent)

SWiM was doing some research yesterday in order to find a new and convenient synthesis of PEA and amphetamine analogues. In a very large book describing a zillion possibilities to obtain aromatic aldehydes (SWiM didn't write down the name... It was German, can't give any more details. Shoot me tongue), he found a (zillion)^2 references to possibly interesting articles. Since SWiM would be banned from this Place if he posted all references (overflow wink ), he presents you one of the more interesting articles: N Blazevic, D Kolbah, B Belin, V Sunjic, F Kajfez. Hexamethylenetetramine, a versatile reagent in organic synthesis. Synthesis :3 (1979) 161-176.
Here are some notes/remarks/theoretical possibilities SWiM found when reading the article:

1. Delépine reaction
The Delépine reaction is the conversion of alkyl halides to primary amines: R1R2-CH-X --> R1R2-CH-NH2. Secondary amines are not expected contaminants. Typical procedure:
1-(alfa-aminoacetyl)-3-hydroxy-4-methoxybenzene hydrochloride: A mixture of 1-chloroacethyl-3-hydroxy-4-methoxybenzene (7.0 g, 0.035 mol) and EtOH (400 mL) is stirred at room temperature for 24 h. The resultant, off-white crystals are filtered, washed with cold EtOH, and heated under reflux in EtOH (300 mL)/concentrated HCl (20 mL) for 2 h. On cooling of the mixture, the product separates as white crystals; yield: 7.0 g (90%); mp 250-252 C (decomposes) with darkening at 230 C.
There is a detailed page regarding the Delépine reaction on Rh's site.

2. Reactions of oxiranes with hexamethylenetetramine (HMTA) in chloroform
The reaction of substituted oxiranes (epoxides) with HMTA is a modification of the Delépine reaction. Reaction of an oxirane with HMTA yields 2-amino-1-hydroxy alcohols, while reacting oxiranes with primary, secondary or tertiary amines yields the isomere 1-amino-2-hydroxy as well.

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 wink ).

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!

Ave Hive, synthetisandi te salutant!
(Hive Bee)
11-20-02 14:01
No 381555
      Good old Cyrax is interested  Bookmark   

Ph-C---C + HMTA ---> Ph-CH-CH2-NH2
       \ /                           |
        O                           OH
Yield: 100%  (cf. H J Roth, A Brandau. Arch Pharm 292 (1959) 761

That looks mighty interesting.  A post of the procedure would be appreciated very much.
Is Arch. Pharm. the same journal as Arch. Pharm. Res.?  If it is, I wonder if you could look up a little article for me smile.
(Hive Bee)
11-20-02 14:11
No 381558
      GC_MS  Bookmark   

2. Reactions of oxiranes with hexamethylenetetramine (HMTA) in chloroform

This is relly what I was looking for, awsome, 4-Me-aminorex, here we come....

"Turn on, Tune in and Drop Out"
(Hive Bee)
11-20-02 14:24
No 381566
      On the aminolysis of styroloxides
(Rated as: excellent)

Here are some fragments from:
HJ Roth, A Brandau. Ueber die Aminolyse von Styroloxyd: Darstellung von Phenylaminoaethanolen. Archiv der Pharmazie 292 (1959) 761-777.

The uebertranssetzung is by SWiM. He picked some interesting notes from the article, i.e. this is NOT the complete text.

1908 - M Tiffeneau and E Fourneau report quantitive conversion of styreneoxide with dimethylamine to 1-phenyl-2-dimethylamino-ethanol [2].
1945 - W S Emerson obtained the same product by reacting styreneoxyde with NH3, but in 18% yield. Better yields were obtained (up to 80%) when working with primary and secondary amines to obtain the N-substituted compounds [3].
1950 - W B Wheatley used iPr-amine and obtained 1-phenyl-2-isopropylamino-ethanol in a 71% yield [4].
1951 - W Beck converted methyl benzylamine to 1-phenyl-2-methylbenzylamino-ethanol with 83% yield [5].
1952 - C L Browne and R E Lutz converted styreneoxyde with benzylamine and obtained two isomeres [6].
1954 - J A Castro converted styreneoxyde with NH3 and reports two isomeres as well: 1-phenyl-2-amino-1-ethanol and 1-phenyl-1-amino-2-ethanol (3.6:1 ratio) [7].
1956 - U Hoffman, H H Kuhn and H Brugger describe in a patent (Anmeinung D 19814 ???) the synthesis of several aminoalcohols from styreneoxyde using NH3.
1957 - W Ziegenbein and W Franke obtained 1-phenyl-2-N-ethanol-1-lactame by reacting styreneoxyde with lactame [9].

When the aminolysis is applied by reacting styreneoxyde with hexamethylenetetramine (HMTA) and with purine bases, only 1-phenyl-2-amino-1-ethanol derivatives are formed. When NH3 ir benzylamine are used, isomeres are detected:

Ph-CH---CH2  +  HN---R  --- 1 --->  Ph---CH---CH2---NR2
     \ /         |                       |
      O          R                       OH

                        --- 2 --->  Ph---CH---CH2---OH

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-

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.

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 tongue. Aminolysis of phenylpropenyl oxides? Styrene analogues that can be converted to PEAs?

Ave Hive, synthetisandi te salutant!
(Hive Bee)
11-20-02 14:34
No 381568
      Damn, that 's a bummer.  Bookmark   

Damn, that 's a bummer.  I thought the yield would be 100 % but it seems to be 29 %.  They probably meant 100 % stereoselectivity ...
(Hive Bee)
11-20-02 15:18
No 381577
      grms  Bookmark   

Damn, that 's a bummer.  I thought the yield would be 100 % but it seems to be 29 %.  They probably meant 100 % stereoselectivity ...

No, but the author wrote things down in such a way that the reaction looks rather fabulous... The reaction consists of 2 steps:
1. formation of the hexaminium chloride
2. formation of the 2-amino-1-ethanol derivative using the hexaminium chloride as precursor.
The 100% yield is for step 2 only. So it probably is step 1 that lowers your yield (in this case).
Another one: H J Roth. Eine neue Methode zur Herstellung von 1-Amino-2-hydroxy-Verbindungen ohne Bildung von Di-und Tri-(oxyalkyl)-aminen als Nebenprodukte. Arch Pharm 292 (1959) 76-82.
(some outtakes):

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.

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? wink

Ave Hive, synthetisandi te salutant!
(Hive Bee)
11-20-02 16:11
No 381596
      OK, I see. Thanks for the clarification.  Bookmark   

OK, I see. Thanks for the clarification.

The last reaction you posted looks rather dangerous, since there is a phosgene evolution ... phosgene ... yummy
(Hive Bee)
11-20-02 19:11
No 381623
      phenylethanol amines  Bookmark   

Hoffmann, Kuhn, Brugger: Verfahren zur Herstellung von Phenyläthanolaminen Patent DE975297
(Chief Bee)
11-21-02 20:26
No 381907
      Hexamethylenetetramine (HMTA, Hexamine)
(Rated as: excellent)

The article referred to in the post at the top of this thread: Post 381544 (GC_MS: "Hexamethylenetetramine: a review", Chemistry Discourse)

Hexamethylenetetramine, a versatile reagent in organic synthesis
N Blazevic, D Kolbah, B Belin, V Sunjic, F Kajfez
Synthesis, No. 3, pp. 161-176 (1979) (../rhodium/pdf /hexamethylenetetramine.pdf)