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Author Topic: Ok - N-Phthaloyl Protecting Group for FC-Acylation  (Read 84 times)

no1uno

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Ok - N-Phthaloyl Protecting Group for FC-Acylation
« on: April 16, 2011, 01:17:04 AM »
The N-Phthaloyl-amino acids can and have been used widely for the stereoselective bulk preparation of various Cathinones, Ephedrines and even Amphetamines. The fly in the ointment is the conditions needed for the removal of the N-Phthaloyl group, which until now has reportedly been only really feasible with hydrazine. Then I was looking about today, for some reason or another, and came across a paper on the stereoselective introduction of deuterium into phenylalanine(s), which used a N-Phthaloyl group which was then removed using AcOH/HCl in what I suspect where decent yields. Anyone got anything further on this? If it works, it looks like there is a real prospect of using N-phthaloylalanine with all sorts of substituted benzenes might be a goer (in fact, it will require a little more work on a decent route from Naphthalene to Phthalic Acid/Anhydride as well).

I realize that FC Acylation to prepare bulk Cathinones, etc. would require the N-phthaloylalaninoyl chloride, but such a straightforward method should be investigated provided we aren't having to use nasty chemicals to get rid of the N-phthaloyl group.
« Last Edit: April 16, 2011, 01:19:43 AM by no1uno »
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letters

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Re: Ok - N-Phthaloyl Protecting Group for FC-Acylation
« Reply #1 on: April 17, 2011, 11:17:18 AM »
I have no direct experience with the phthalaoyl group, however there are other choices for a protecting group for alaninen-trifluoroacetyl works well and is easy to remove. fmoc works well as well. You can even prepare the anhydride of an amino acid to use it in friedel crafts.
1. Facile Approach to Enantiomerically Pure Amino Ketones by Friedel Crafts Aminoacylation and Their Conversion into Peptidyl Ketones. J. Org. Chem. 2001, 66, 7002-7007.

2. Friedel-Crafts a-Aminoacylation  of Alkylbenzene with a Chiral N-Carboxy-a-amino  Acid Anhydride without Loss of Chirality. J. Org. Chem. 1992,57,7334-7338.

3. Friedel-Crafts Acylation with N-(Trifluoroacetyl)-a-amino Acid Chlorides. Application to the Preparation of b-Arylalkylamines and 3-Substituted 1,2,3,4-Tetrahydroisoquinolines. J. Org. Chem., Vol. 49, No. 22, 1984, 4107-4111.

4.N-(Trifluoroacety1)-a-amino  Acid Chlorides as Chiral Reagents for
Friedel-Crafts  Synthesis. J. Org.  Chem. 1985,50, 3481-3484.

Another one is with ethyl chloroformate to give the ethyl carbamate as a protecting group, deprotection is done with KOH (which means that unless you reduce or protect your carbonyl, you will get dimerization) -
5. Synthesis and Antitumor Activity of Enantiomerically Pure [1,2-Diamino-1-(4-fluoro-phenyl)propane]dichloroplatinum(II) Complexes. Arch. Pharm. Pharm. Med. Chem. 2002, 5, 229–239.

My Favorite FC acylation procedure is the one depicted in Org. Lett., 2008, Vol. 10, No. 13, 2645 2648 :
Mild, Ef?cient Friedel Crafts Acylations from Carboxylic Acids Using Cyanuric
Chloride and AlCl3.
It works well and prepares the acid chloride insitu. One example shows the use of a benzoyl protected amino acid undergoing an intermolecular FC acylation avoiding the possible indole-skeleton formation and forming only C-C new bonds - 85% isolated yield, suggesting this is a good protecting group for amines! IIRC the benzoyl group is removed via hydrogenation

no1uno

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Re: Ok - N-Phthaloyl Protecting Group for FC-Acylation
« Reply #2 on: September 09, 2011, 04:01:42 AM »
Another interesting article from Glennon, et al on the efficacy of oxygenated (ie. cathinone/ephedrine) analogues of the DOB series. While a benzylic OH group led to major differentiation in the agonist-efficiency between l/d analogues, it raises the question once again whether the aminoketone (ie. the cathinone variant) would have useful agonist properties. As posited by Shulgin however, without an N-substituent there would be dimerization between the ketone and the amine, however, what of the N-(2-methoxy)benzyl substituted variants?

It is interesting as it would remove a potentially problematic reduction step (from the cathinone from the FC-acylation to the desoxy variant). It would certainly be something to investigate, given that the existence of an O/OH group on the benzylic carbon in the 2-C/DOB series doesn't appear to fuck with receptor binding.
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atara

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Re: Ok - N-Phthaloyl Protecting Group for FC-Acylation
« Reply #3 on: September 09, 2011, 05:22:04 PM »
If you want to acylate using an amino acid I think an azlactone would be better than a protecting group:

http://en.wikipedia.org/wiki/Erlenmeyer-Plöchl_azlactone_and_amino_acid_synthesis

Switch glycine for alanine in that reaction and you go directly to cathinone.
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