FC Acylation with N-Phthaloyl-alanylchloride

There are a number of papers on the stereospecific synthesis of various substitued (and unsubstituted) PEA's or amphetamines via the FC acylation of the aromatic substrate with N-protected alanyl chloride.

The problems however seemed insurmountable, the procedures utilized protecting groups that were (1) derivatives of phosgene (ie. Rapaport, et al), or (2) Trifluoroacetic acid - by no means as off putting as phosgene, but not exactly OTC either...

Now the paper I'm discussing deals with using N-phthaloyl-alanine, chlorinating that (SOCl2/POCl3 can both be utilized apparently) to give the N-phthaloyl-alanylchloride.

Iron (III) Chloride is the FC-Acylation catalyst, reason being, it doesn't cause the demethylation of the alkoxy groups.

Of some serious note, the author's discuss the making of N-phthaloyl-2,5-dimethoxy-cathinone by this procedure. Unfortunately, in order to utilize this procedure to get to the active isomer (R)-2,5-dimethoxyamphetamine, one would have to use unnatural d-alanine, the l-alanine gives the (S)-product.

Of course, given that the intermediate product is a cathinone, which I believe are easily racemized (indeed, it is reportedly a serious problem even when working up the solution), then the unwanted isomer (if one started with the available d,l-alanine, presumably half the product would be the unwanted isomer), could then be recycled, racemized and reworked.

Deoxygenation is per Rapoport, et al's general procedure, 4h, 55psig/~4Atm H2, 10% Pd/C, 1N HCl - reportedly giving the desoxyephedrine in about 90% yield.

What is needed is for some nice person, with a good understanding of organic chemistry and the German language, to provide a workable translation of the paper provided (Here is the Google translation).

BTW - the article in question is also attached (paper 2, Effenberger... I have provided the google translation as notes at the end of each paragraph).

PS I know this is a long way from being workable at the present time, that's not an issue for mine, I like to ensure the information is available if people want it

Attachment: Buckley.Rapoport.a.AminoAcids.Ephedrine.pdf (1MB)
This file has been downloaded 806 times

Attachment: Effenberger.Steegmuller.FC.Acylation.N.PhthalloylAlanine.pdf (661kB)
This file has been downloaded 583 times

Attachment: McClure.etal.ChiralAminoAcids.2.pdf (726kB)
This file has been downloaded 587 times

Attachment: Mclure.etal.Chiral.aAminoAcids.FC.Acylation.Alanine.pdf (382kB)
This file has been downloaded 551 times

Attachment: Nordlander.etal.TFA.a.AminoAcids.for.FC.Acylation.pdf (566kB)
This file has been downloaded 664 times

Attachment: OsorioOlivares.etal.2Step.Method.Prep.Homochiral.Cathinones.pdf (216kB)
This file has been downloaded 1021 times

Attachment: US4618710.Rapoport.etal.Optically.Pure.Synthesis.Ephedrine.pdf (309kB)
This file has been downloaded 606 times

Attachment: Chambers.etal.Enantiospecific.Synthesis.FLY.pdf (108kB)
This file has been downloaded 649 times

[Edit]

What is also of interest, is that Shulgin, et al, used the N-phthaloyl protecting group when attaching labeled I[131] to 2,5-dimethoxyamphetamine... So presumably it would be just as effective for the attachment of chlorine/bromine/etc.

I'll throw up another paper, on the use of phthalic acid (instead of phthalic anhydride) to prepare the N-phthaloyl-alanine

[Edited on 10-1-2010 by unome]

Attachment: Zavyalov.etal.Synthesis.N.Phthaloyl.Amino.Acids.pdf (78kB)
This file has been downloaded 856 times

Hi unome,

Interesting topic. Apart from the papers you refer to (I haven't look them up yet) there is also an old paper* from a Croatian group describing a high yielding reaction between N-Phthaloyl-D-alanyl chloride and benzene (AlCl3 catalysis, 93% yield) which is also used as a solvent. I don't have the paper but luckily a useful abstract is available:

The correlation of configuration of optically active norpseudoephedrine and alanine

Abstract

D-MeCHRCOCl [R = .omicron.-C6H4(CO)2N throughout this abstr.] (5 g.) in 20 ml. C6H6 added with stirring to 30 ml. C6H6 and 7.03 g. AlCl3 at 70 at such a rate as to maintain const. refluxing, the mixt. refluxed 3 hrs., cooled, and treated with 30 g. ice and 4 ml. concd. HCl, the aq. layer extd. with C6H6, the ext. washed with H2O, followed by NaHCO3 soln., dried over MgSO4, and evapd. in vacuo gave 8.5 g. residue, which crystd. from EtOH yielded 5.4 g. D-PhCOCHRMe (I), m. 81-2 (75% EtOH), [.alpha.]20D 165.5 (c 1.44, EtOH); 2,4-dinitrophenylhydrazone, m. 210-12 (EtOH). Similarly was prepd. L-I, m. 81-2, [.alpha.]20D -160.5 (c 2.0, EtOH). D-I (3.5 g.), 7 g. (iso-PrO)3Al, and 70 ml. abs. iso-PrOH refluxed 5 hrs. with the removal of the theoretical amt. of Me2CO, the iso-PrOH removed in vacuo, the residue hydrolyzed with 45 g. [CH(OH)CO2H]2 in 120 ml. H2O in the presence of 20 ml. C6H6, the aq. layer extd. with C6H6, the combined C6H6 solns. dried and evapd. in vacuo, and the residue (3.3 g.) recrystd. from 7 ml. EtOH gave 2.1 g. D-threo-PhCH(OH)CHRMe (II), m. 159-60 (EtOH), [.alpha.]20D -111.3 (c 0.93, C6H6). Similarly was prepd. L-II, m. 156-7, [.alpha.]20D 108 (c 1.22, C6H6). A mixt. of L-II and D-II m. 130-2. D-II (1.44 g.) refluxed 2 hrs. with 14 ml. EtOH and 14 ml. N2H4.H2O in EtOH, the solvent removed in vacuo, the residue treated for 10 min. at 50 with 25 ml. 10% HCl, kept 1 hr. at room temp., the phthalyl hydrazide filtered off, the filtrate evapd. in vacuo (bath below 50), and the residue (1.44 g.) crystd. from 5 ml. EtOH and 16 ml. Et2O gave 0.82 g. D-threo-norephedrine hydrochloride (III), m. 178-9 (1:2 EtOH-Et2O), [.alpha.]30D -42.9 (c 1.825, H2O). Similarly was prepd. L-III, m. 175-6, [.alpha.]20D 42.1 (c 2.35, H2O). A mixt. of L-III and D-III gave the same spot on paper chromatography for Rf 0.78 (4:1:5 BuOH-HOAc-H2O) as the authentic DL-III, m. 168-9 (undepressed with DL-III, but strongly depressed with DL-erythro-norephedtine hydrochloride).

*: Fles, D.; Markovac-Prpic, A. Croatica Chemica Acta (1957), 29 183-7

Obviously, N-Phthaloyl-alanyl chloride can be used in place of the corresponding trifluoroacetyl and other protecting groups. As you mentioned, the aromatic keto group can be easily reduced and there are many examples in the litterature using hydrogenation over Pd/C and the yields are high.

That also looks interesting, what suprises me - GREATLY - is that those who spend their entire lives working out how to achieve that specific reduction (albeit from the midpoint alcohol), never see the potential They throw all sorts of conditions at the substrates involved and crow about 50-60% yield...

BTW I wonder if the MW CTH procedure attached (reportedly used for debenzylation IIRC, so I suspect it would work) could be utilized instead. Seems like a neat, clean workaround for those lacking pressure equipment.

Attachment: Banik.etal.MW.Assisted.Rapid.Simplified.CTH.pdf (206kB)
This file has been downloaded 654 times

[Edit]

I also uploaded the PDF of Dr Franz Effenberger, et al's, American Patent #4,945,168, which essentially appears to provide an English language version of what he described in the paper I mentioned upthread.

Taken from page 3/6 in the Patent (Attached):

Example 4

A solution of 4.38g (20.0 mmole) N-phthaloyl-(S)-alanine in 120mL of 1,2-dichloroethane* was combined with 4.58g (22.0 mmole) phosphorus pentachloride** at 0'C. and agitated for 4 hours at room temperature. After the addition of another 120mL 1,2-dichloroethane, a tenth of the solution was rapidly added to an agitated solution of 3.32g (20.0 mmole) hydroquinone diethylether and 320mg iron-(III)-chloride (10 mole percent) in 80mL 1,2-dichloroethane. The reaction mixture was heated to 50'C and the remaining solution of acid chloride was added dropwise in a continuous manner within 12 hours. Then the mixture was agitated 12 hours further at 50'C. and then cooled down to 0'C. 100mL 1N hydrochloric acid cooled down to 0'C. was added and the mixture agitated 24 hours at room temperature. The aqueous phase was separated off and extracted twice with 40mL of methylene chloride per extraction. The combined organic phases were washed with 150mL saturated, aqueous sodium hydrogen carbonate solution and then with water. Then it was dried over sodium sulfate. After removal of the solvent at 40'C. under reduced pressure, the product was chromatographed over a silica gel column. After the solvent was removed again, the product crystallized when left standing in a refrigerator. 5.33g (73% of theory) (S)-2,5-diethoxyphenyl-(1-phthalamidoethyl)-ketone*** with a melting point of 92-93'C were obtained.
[a]20D:+25.9' (c=2, CHCl3)

* They claim a range of chlorinated organic solvents can be utilized, including DCM

** According to Garage_Chemist, the ONLY product of chlorinating RP (Red Phosphorus)

*** aka N-phthaloyl-2,5-diethoxycathinone.

Attachment: US4945168.Effenberger.EtAl.Method.of.Preparing.Aryl.1.Phthalamido..Alkylketones.pdf (297kB)
This file has been downloaded 568 times

[Edited on 13-1-2010 by unome]