A-alkylamino acids

Difficult N-acylations, such as those of A-alkylanilines or a-alkylamino acid derivatives, are most conveniently performed with acyl halides in non-nucleophilic solvents (e.g. DCM, DCP) in the presence of pyridine or DIPEA [13]. Acyl halides can be prepared on insoluble supports under conditions similar to those used in solution. Typical reagents for the preparation of acyl chlorides include oxalyl chloride [19-21], thionyl chloride [22,23], and triphosgene [13]. Anhydrous solvents must be used for all wash-... 

Illustrative examples of the acylation of support-bound amines with carbodiimides as coupling agents are listed in Table 13.3. Difficulties are usually encountered in the acylation of a-alkylamino acid derivatives (which are significantly less nucleophilic than simple secondary amines Entries 3 and 4) and Al-alkyl (Entries 5 and 6) or iV-aryl anilines. Acylations with haloacetic or related acids containing a leaving group prone to nucleophilic displacement should not be performed with the aid of HOBt and bases because O-alkylation of HOBt by the product occurs readily. 

Diazepanones have been prepared on insoluble supports by intramolecular nucleophilic cleavage, by intramolecular Mitsunobu reaction of sulfonamides with alcohols, and by intramolecular acylations (Table 15.36). As in the case of azepines, these reactions do not always proceed smoothly, and care must be taken to prevent potential side reactions from occurring. For instance, intramolecular acylations in peptides containing aspartic acid (Entry 2, Table 15.36) will generally lead to the formation of suc-cinimides (see Table 13.20) unless A-alkylamino acids are used. 

Whereas preparation of a-amino acid derivatives by asymmetric allylation of an acyclic iminoglycinate gave a modest enantioselectivity (62% ee) in an early investigation [189], the use of conformationally constrained nucleophiles in an analogous alkylation resulted in high selectivities (Scheme 8E.43) [190], With 2-cyclohexenyl acetate, the alkylation of azlactones occurred with good diastereomeric ratios as well as excellent enantioselectivities. This method provides very facile access to a variety of a-alkylamino acids, which are difficult to synthesize by other methods. When a series of azlactones were alkylated with a prochiral gem-diacetate, excellent enantioselectivities were uniformly obtained for both the major and minor diastereom-ers (Eq. 8E.20 and Table 8E.12). 

Typical procedure. (R,S)-4-t-ButYl-2,3,4,5-tetrahYdro-3-methYl-i,3-oxazole-2,5-dione 1219 [897] According to [887] To a solution of (R,S)-a-alkylamino acid hydrochloride 1218 (100 mg, 0.55 mmol) in dichloromethane (30 mL) was added triethylamine... 

N-Alkylamino acids. Table 12 and Fig. 13 show the separation of enantiomeric A -alkylamino acids and -formyl-ter/-leucine. Further examples have been published recently (102,170,195). In contrast to the examples described above, the detection of 7///-dimethylphenylalanine was achieved with iodine. The enantiomeric separation of A -carbamoyltryptophan has also been described (176). 

Formation of Schiff-Bases. Reaction of an amino acid and an aldehyde oi ketone gives a Schiff-base in neutral or alkaline solution, and following reduction gives the corresponding Ai-alkylamino acid. 

B. Reactions.—(/) Nucleophilic Attack at Phosphorus. A reinvestigation of the reaction between phosphorus trichloride and t-butylbenzene in the presence of aluminium chloride has shown that the product after hydrolysis is the substituted phosphinic acid (11), and not the expected phosphonic acid (12). Bis(A-alkylamino)phosphines have been reported to attack chlorodiphenyl phosphine with nitrogen, in the presence of a base, to give bis-(A-alkyl-A-diphenylphosphinoamino)phenylphosphines (13). In (13), the terminal phosphorus atoms are more reactive than the central one towards sulphur and towards alkyl halides. 

Reaction of A -acylamino acids with the Vilsmeier-Haack reagent leads to 2-alkyl-4-[(Af,Af-dimethylamino)methylene]-5(47i)-oxazolones 814. The reactivity of these compounds with various nucleophiles has been studied. Primary alkylamines undergo amine exchange with 814 to afford 2-alkyl-4-[(alkylamino)methylene]-5(4/i)-oxazolones 815 (Scheme 7.250). ° ... 

Bis-p-nitrophenyl malonate (55M29) reacts with a-alkylamino-isobutyr-onitriles in xylene to give derivatives (16b) of tetramic acids with yields of 30-50% (86UP1 88UP1). The reaction of derivatized malonic acids with a-amino acid esters to 3-alkoxycarbonyl-l,5-dihydro-4-hydroxy-2-pyrrolones presents the same problems (see Section III). (See Fig. 8.)... 

One of the more important uses of thioureas has been in the preparation of 2-imino-4-thiazolidinones, first reported by Meyer135 and Andreasch,136 138 via reaction with a-halo acids or esters. This reaction has been covered by Brown139 in a review on 4-thiazolidinones which appeared in 19(51, and, therefore, will not be discussed in detail here. The corresponding reaction between a-halo acids or esters and scleno-ureas to produce 2-iminoselenazolidin-4-ones is also known and has been reviewed.77-78 Akerblom140 has attempted to clear up some of the confusion in the literature on whether 3-alkyl-2-iminothiazolidin-4-ones (63) or 2-alkylamino-2-thiazolin-4-ones (64) are formed from 1-alkyl-thioureas and chloroacetic acid. She found that the reaction in water... 

V-acylaziridine-2-imides to oxazoline-4-imides, followed by hydrolysis of these latter compounds, has been used586 to afford chiral / -hydroxy-a-amino acid precursors. It has been suggested587 that the observed thermal rearrangement of c/.s-aziridinyl ketone tosylhydrazones (449) to 5-alkylamino-3,5-diphenyl-l-tosyl-2-pyrazolines (450) is... 

R.M.Herbst et al, JOC, 16,139-49(1951) CA 45, 662 >—31(1951) (18 n) (Prepn of various 1— alkyl—5—aminotetrazoles by the interaction of alkylcyanides with hydrazoic acid in benzene soln in the presence of a coned acid some props of alkylamino- and arylaminotettazoles) 4)L.A. Burkardt D.V. Moore, AnalChem 24,1579-85... 

The gold(I) complex is prepared in situ by the reaction of (1) with bis(cyclohexyl isocyanide)gold(I) tetrafluoroborate (2), typically in anhydrous dichloromethane. The dihydrooxazolines obtained provide a ready access to enantiomerically pure p-hydroxy-a-amino acid derivatives. High diastereo- and enantios-electivity are generally maintained with a wide variety of substituted aldehydes, and a-isocyanoacetate esters. N,N-Dimethyl-a-isocyanoacetamides and a-keto esters have been substituted for the a-isocyanoacetate ester and aldehyde component, respectively, sometimes with improved stereoselectivity. The effect of both the central and planar chirality of (1) on the diastereo- and enantioselectivity of the gold(I)-catalyzed aldol reaction has been studied. The modification of the terminal di-alkylamino group of (1) can lead to improvements in the stereos-... 

Ethyl 3-ethoxy-a-nitroacrylate with 1,1-diphenylhydrazine in ethanol followed by heating has been shown to give l,4-bis(diphenylamino)-2,5-diethoxycarbonyl-l,4-dihydropyrazine (1586). A small amount of 2,5-dicyano-l,4-bis(dimethylamino)-1,4-dihydropyrazine was obtained from the reaction of 2-chloro-3-(2, 2-dimethyl-hydrazino)propionitrile [(Me)2NNHCH2CH(Cl)CN] with sodium hydride (1587). Hexaalkyl-l,4-dihydropyrazines and other 1,4-dialkyl-1,4-dihydropyrazines can be obtained by thermolysis of the products of reaction of a-(alkylamino)carboxylic acid esters with alkylmagnesium bromide. Thus the reaction of ethyl a-s-butyl-aminopropionate with ethylmapesium bromide, followed by heating in vacuo to 250-300°, gave 2,5-dimethyl-3,6-diethyl-l,4-di-s-butyl-l,4-dihydropyrazine (1588). 

A series of A-alkylamino fumarates have been oxidized by LTA in the presence of trifluoroaoetic acid as a catalyst, leading to mixtures of pyrroles, pyridones and pyrrolo [3,2-6]pyrroles given in Scheme 49" . In some cases acyclic oxidative dimers were isolated. The enamine molecules in them are linked through their -carbon atoms (Scheme 49). 

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