Trifluoroacetyl amides

Trifluoroacetyl amides are an easily installed and cleaved protecting group for amines and anilines. 

A suspension of trifluoroacetyl amide (158 mg, 0.434 mmol) and potassium carbonate (310 mg, 2.25 mmol) in methanol-water (12 1,13 mL) was heated at reflux for 2 h. The solvent was removed in vacuo, the residue was dissolved in dichloromethane (30 mL), and water (20 mL) was added. The aqueous layer was extracted with a further 2 portions of dichloromethane (30 mL). The combined organic fractions were dried (MgSO4) and the solvent was removed in vacuo to yield the deprotected amine as a yellow oil (100 mg, 86%). 

Synthesis from d-glucose A stereospecific synthesis of nectrisine (1) has been achieved from diacetone D-glucose by conversion to 3 (Scheme 1). Catalytic reduction of 3 followed by acylation with trifluoroacetic anhydride afforded the trifluoroacetyl amides 4 (82%) and 5 (13%). Removal of the isopropylidene group from 4 afforded 6, which was subjected to oxidation with NaI04 followed by removal of the benzyl group and subsequent deacylation of the formyl and trifluoroacetyl groups to produce 1. 

Finally, it has been found only recently that the intramolecular oxidative coupling of appropriately substituted monophenolic tetrahydrobenzyliso-quinolines induced by VOF3-TFA constitutes one of the simplest and most efficient routes to the aporphines. The only limitation here is that the nitrogen atom must be protected as the trifluoroacetyl amide or the borane complex, as illustrated by the two examples shown in Scheme 10.4. The yields are appreciably lower if the amine function is unprotected. ... 

The reaction of diethylene triamine with two equivalents of ethyl trifluoro-acetate gave the crystalline bis(trifluoroacetyl)amide 8 in nearly quantitative yield. Trimerization with trimesoyl trichloride resulted in the desired TFA-6-amine 9. Under the alkaline saponification conditions, however, the free hexaamine underwent a partial rearrangement. This could be demonstrated by addition of Z-Cl (benzyloxycarbonylchloride) in one pot, which led to a mixture of four species 4, and with the target molecule 4 as the main... 

The hydrogeh atom bound to the amide nitrogen in 15 is rather acidic and it can be easily removed as a proton in the presence of some competent base. Naturally, such an event would afford a delocalized anion, a nucleophilic species, which could attack the proximal epoxide at position 16 in an intramolecular fashion to give the desired azabicyclo[3.2.1]octanol framework. In the event, when a solution of 15 in benzene is treated with sodium hydride at 100 °C, the processes just outlined do in fact take place and intermediate 14 is obtained after hydrolytic cleavage of the trifluoroacetyl group with potassium hydroxide. The formation of azabi-cyclo[3.2.1]octanol 14 in an overall yield of 43% from enone 16 underscores the efficiency of Overman s route to this heavily functionalized bicycle. 

The original procedure for the trifluoroacetylation of amino acids used trifluoroacetic anhydride [Acetic acid, trifluoro-, anhydride].4 This reagent, although inexpensive and readily available, has certain disadvantages it is a highly reactive compound and thus has caused undesired reactions such as the cleavage of amide or peptide bonds,5 unsymmetrical anhydrides are formed between the newly formed A-trifluoroacetylamino acids and the by-product trifluoroacetic acid, and excess trifluoroacetic anhydride has caused racemization of asymmetric centers. 

These reactions involve a diazonium ion (see 12-47) and are much faster than ordinary hydrolysis for benzamide the nitrous acid reaction took place 2.5 x lo times faster than ordinary hydrolysis. Another procedure for difficult cases involves treatment with aqueous sodium peroxide. In still another method, the amide is treated with water and f-BuOK at room temperature. " The strong base removes the proton from 107, thus preventing the reaction marked k j. A kinetic study has been done on the alkaline hydrolyses of A-trifluoroacetyl aniline derivatives. Amide hydrolysis can also be catalyzed by nucleophiles (see p. 427). 

Alternatively, alkylation of 4-benzyl-2-(trifluoromethyl)-5(2//)-oxazolone 16 in the presence of mild base using active alkyl halides as electrophiles occurs at C-4 " Subsequent aminolysis of a 4,4-dialkyl-5(4f/)-oxazolone like 17 gave an Al-(trifluoroacetyl)-a,a-dialkylglycine amide 18 that was used to prepare important peptides incorporating an a,a-dibenzylglycine unit (Scheme 7.5). 

Heck cyclization with concomitant deprotection of the trifluoroacetyl group to form the indoleacetic methyl ester 68. Compound 68 was hydrolyzed and then treated with PCI5 followed by dimethylamine to give the amide 69, which was reduced with LiAlHi to afford almotriptan (5). 

Following their syntheses of ( )-pancracine and related alkaloids (vide supra), Hoshino et al [106] had described a different approach involving radical cyclisation of an isoquinoline derivative which permitted a rapid assembly of keto-5,11-methanomorphanthridine skeleton. The syntheses of 413, 414 and 415 commenced with the known 4-hydroxy-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoIine (439) (Scheme 62). Subsequent to protection of the amino group as the trifluoroacetyl derivative, the amide alcohol 440 was converted into the amide thioether 441, by reaction with phenylthiol in the presence of zinc iodide. Alkaline hydrolysis of 441,... 

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