Azlactone preparation

Monsanto s commercial route to the Parkinson s drug, L-DOPA (3,4-dihydroxyphenylalanine), utilizes an Erlenmeyer azlactone prepared from vanillin. The pioneering research in catalytic asymmetric hydrogenation by William Knowles as exemplified by his reduction of 24 to 25 in 95% ee with the DiPAMP diphosphine ligand was recognized with a Nobel Prize in Chemistry in 2001. ... 

Tryptophans can also be prepared by reduction of a,(3-dehydrotryptophans. These can be obtained by a classical azlactone type synthesis from derivatives of indole-3-carboxaldehyde. These reactions usually rquire an iV-EW substituent and the yields are modest[15]. 

This azlactone is prepared readily from benzaldehyde according to the procedure given for the azlactone of a-ben-zoylamino-/3-(3,4-dimethoxyphenyl)-acrylic acid (Org. Syn. 13, 8). From 53 g. (0.5 mole) of benzaldehyde, 89.5 g. (0.5 mole) of hippuric acid, 41 g. of fused sodium acetate, and 153 g. of acetic anhydride there is obtained 78-80 g. (62-64 per cent yield) of an almost pure product melting at 165-166° (corr.). This material is sufficiently pure for use in the preparation of phenylalanine. By crystallization from 150 cc. of benzene a product melting at 167-168° (corr.) is obtained. 

The azlactones of a-benzoylaminocinnamic acids have traditionally been prepared by the action of hippuric acid (1, Ri = Ph) and acetic anhydride upon aromatic aldehydes, usually in the presence of sodium acetate. The formation of the oxazolone (2) in Erlenmeyer-Plochl synthesis is supported by good evidence. The method is a way to important intermediate products used in the synthesis of a-amino acids, peptides and related compounds. The aldol condensation reaction of azlactones (2) with carbonyl compounds is often followed by hydrolysis to provide unsaturated a-acylamino acid (4). Reduction yields the corresponding amino acid (6), while drastic hydrolysis gives the a-0X0 acid (5). ... 

Modification of the Erlenmeyer reaction has been developed using imines of the carbonyl compounds, obtained with aniline," benzylamine or n-butylamine. Ivanova has also shown that an A-methylketimine is an effective reagent in the Erlenmeyer azlactone synthesis. Quantitative yield of 19 is generated by treatment of 3 equivalents of 2-phenyl-5(4ff)-oxazolone (2) (freshly prepared in benzene) with 1 equivalent of iV-methyl-diphenylmethanimine (18) in benzene. Products resulting from aminolysis (20), alkali-catalyzed hydrolysis (21), and alcoholysis (22) were also described. 

Kirk and coworkers recently reported preparation of 6-flouro-meta-tyrosine 29 based on an Erlenmeyer-Plochl azlactone strategy from 2-benzyloxy-5-fluorobenzaldehyde. 

Shaw and McDowellhave prepared imidazolone derivatives by cyclization of a-acylamino amides. In a variation of this reaction the azlactone (30) was gradually converted to the hydroxamic acid (31) by methanolic hydroxylamine. Sodium methoxide and hydroxylamine readily gave the acyclic hydroxamic acid (32) which could be cyclized to 31 by dilute acid. Benzyloxyurea has been used in the sjrnthesis of pyrimidine hydroxamic acids (33) by reaction with /S-diketones followed by catalytic hydrogenation of the benzyl group. Protection... 

Several improved methods for the preparation of known unsaturated azlactones as well as some interesting new compounds of this type have been reported. Crawford and Little observed that the direct use of 2-phenyl-5-oxazolone (1) in the Erlenmeyer reaction gave much improved yields (35-74%) of unsaturated azlactones with aliphatic aldehydes and with ketones such as acetone and cyclohexanone [Eq, (1)], The usual procedure of mixing a carbonyl compound, hippuric acid, acetic anhydride, and sodium (or lead) acetate affords poor yields in the aliphatic series. 

Saturated azlactones such as 18 and 29a, whose preparation is discussed in parts 2, b and 3 of this section, are useful intermediates for the synthesis of a variety of j8,j8-disubstituted alanines (32). ... 

A number of new j8-substituted alanines have been prepared from unsaturated azlactones by the usual reduction-hydrolysis procedures. An interesting example is the synthesis of DL-jS-ferrocenylalanine (33). ... 

The preparation of the less stable isomer (53b) of the oxazolone 53a involves a rather tedious procedure. It has been reported that 53a is rapidly isomerized to 53b in 48% hydrobromic acid saturated with gaseous HBr. In this way four azlactones have been converted into their isomers.It has been established, moreover, that the isomerization is radical-initiated and does not involve a carbonium ion intermediate. The isomerization can be reversed by pyridine. ... 

In subsequent studies,22 Sheehan et al. demonstrated that the action of diisopropylcarbodiimide on penicilloate 24, prepared by protection of the free primary amino group in 23 with trityl chloride (see Scheme 6b), results in the formation of the desired -lactam 25 in a very respectable yield of 67 %. In this most successful transformation, the competing azlactonization reaction is prevented by the use of a trityl group (Ph3C) to protect the C-6 amino function. Hydrogenolysis of the benzyl ester function in 25, followed by removal of the trityl protecting group with dilute aqueous HC1, furnishes 6-aminopenicillanic acid (26), a versatile intermediate for the synthesis of natural and unnatural penicillins. 

The method described above may be used for the preparation of a wide variety of butenolides substituted in the arylidene ring with either electron-withdrawing or electron-releasing substituents. y-Lactones such as a-benzylidene-7-phenyl-A 1 -bu-tenolide are isoelectronic with azlactones, but have received much less attention. Like the azlactone ring, the butenolide ring may be opened readily by water, alcohols, or amines to form keto acids, keto esters, or keto amides.7 a,-Benzylidene-7-phenyl-A3,1 -butenolide is smoothly isomerized by aluminum chloride to 4-phenyl-2-naphthoic acid in 65-75% yield via intramolecular alkylation. 

Ethyl o-nitrophenylpyruvate and o-nitrophenylpyruvic acid 14-21 have been prepared by condensation of o-nitrotoluene with diethyl oxalate in the presence of potassium ethoxide,4 14 sodium ethoxide,16-20 or sodium methoxide.21 Sodium ethoxide is less reactive, however, and cannot be substituted successfully for potassium ethoxide in the present procedure, as it gives a very poor yield and poor quality of precipitated sodium salt. With sodium ethoxide the reaction does not appear to go to completion even under the conditions of refluxing ethanol usually employed,16-21 which are considerably more severe than the room temperature conditions employed with potassium ethoxide in the present procedure. o-Nitrophenylpyruvic add has also been prepared by hydrochloric acid hydrolysis of o-nitro-a-acetamino-dnnamic azlactone.4... 

Hydroxyphenylpyruvic acid has been prepared by alkaline hydrolysis of the azlactone of a-benzoylamino- -acetoxycin-namic acid 7 and by a two-step hydrolysis of the azlactone of a-acetamino- -acetoxycinnamic acid.8 p-Hydroxyphenylpyruvic acid has also been prepared by alkaline hydrolysis of 5-( -hy-droxybenzal)-3-phenylhydantoin.9 The procedure described here is adapted from published directions for the preparation of -hydroxyphenylpyruvic-3-C14 acid.5 5-( -Hydroxybenzal)hy-dantoin is prepared according to the method of Boyd and Robson.10... 

Hydroxyphenylpyruvic acid plays an important role in the biogenesis of compounds with a phenylpropane skeleton, and it has been used as substrate in several enzyme studies. Published procedures for its preparation are unsatisfactory in many ways. The alkaline hydrolysis of the azlactone of a-bcnzoylamino- -acetoxycinnamic acid 7 makes necessary a tedious separation of the resulting benzoic acid, and the yield is only 34% based on -hydroxybenzaldehyde. The hydrolysis of 5- ( -hydroxybenzal)-3-phenylhydantoin 9 requires a separation of phenylurea. Finally, the two-step cleavage of the azlactone of a-acetamino- -acetoxycinnamic acid 8 does not proceed easily, and impure products are obtained. In applying this procedure to the synthesis of a carboxyl-labeled -hydroxyphenylpyruvic acid, the overall yield was only 9%.u It must be kept in mind that any prolonged isolation procedure will cause some decomposition of this sensitive compound. 

The now readily available 2-thenaldehydes were utilized for the preparation of azlactones involving the Erlenmeyer synthesis ... 

Saturated 2-vinyl-5(47Z)-oxazolones have been widely used as intermediates for the synthesis of polymeric compounds that will be described in Section 7.3.2.9. Apart from these polymerization reactions, the Diels-Alder reactions of 4-sub-stituted-2-vinyl-5(47/)-oxazolones 134 with cyclopentadiene are reported to give norbomenyl oxazolones 135 that are useful to prepare norbornenyl functionalized resins by azlactone ring-opening addition reactions (Scheme 7.39). 

One of the oldest methods for the preparation of DHAs is the ring opening of unsaturated azlactones by attack of a nucleophile on the carbonyl group. Several methods for the synthesis of unsaturated azlactones (Azl) have been developed over the years and the chemistry of these important intermediates has been reviewed/1,2 Following are the methods of their synthesis that have remained in use during the last few decades. 

The preparation of the first unsaturated azlactone was reported in 1883 by Plochl/40 who condensed benzaldehyde with hippuric acid in presence of acetic anhydride. This approach was later used by Erlenmeyer/41 who extended the procedure to include other aldehydes and also established the usefulness of azlactones as intermediates in the synthesis of DHAs. The method involves the condensation of an A-acylglydne 4 with aldehydes and ketones in the presence of acetic anhydride and anhydrous sodium acetate (Scheme 2)J41 t5l Other catalysts such as copper(II) acetate/46 lead acetate/47,48 potassium carbonate/49 or potassium hydrogen carbonate 50 have also been used. The reaction proceeds via formation of an azlactone 5, which then condenses with the appropriate aldehyde or ketone to give unsaturated azlactone 6. Reaction of 6 with a nucleophile such as OH, OR, or NHR leads to the corresponding A-acyl-DHA derivatives 7. Reaction with the sodium salt of an amino acid gives a DHA containing dipeptide acid. 51 ... 

Thus, the A-chloroacetyl derivatives of Phe 55 and Leu,151 for example, when warmed with acetic anhydride, readily form the requisite unsaturated azlactone by the elimination of one molecule each of water and hydrogen chloride. A series of DHA derivatives of Phe, Tyr, Leu, Nle, Val, and Ala were prepared by this method. However, this method has not been used routinely to prepare DHA derivatives. 

In this case, the amino acid is already oxidized at the (3-position and elimination of the hydroxy group, as the acetate, generates the double bond. Reaction of the unsaturated azlactone and the free base of an amino acid ester produces the dipeptides containing APhe. This approach has been extensively used in the preparation of a series of APhe containing peptides15 63 ... 

Several attempts have been made, especially in recent years, to oxidize saturated to unsaturated azlactones. 64 The oxidation of saturated azlactone 13 with DDQ or o-chloranil in the presence of collidine as a weak base affords the unsaturated azlactone 14 in 40-50% yield (Scheme 5). Breitholle and Stammer 65 reported the preparation of unsaturated azlactone 16 by dehydrobromination of the bromopseudoazlactone 15 (Scheme 5). The pseudoazlactones derived from Ala and Abu tend to dibrominate, but careful reaction conditions allowed their isolation in acceptable yields. 65 This procedure is applicable to the preparation of derivatives of AAla, AAbu, AVal, and ALeu. 66 ... 

An alternative to the azlactone procedure for the preparation of short-chain dehydropeptides 19 is offered by the direct condensation of an a-oxo acid 17 on heating with one equivalent of a carboxylic acid amide or by the treatment of an a-oxo acid 17 with a nitrile in the presence of dry HC1 gas (Scheme 6). If the former reaction proceeds with the condensation of two molecules of amide per molecule of a-oxo acid, then the corresponding a,a-bis(acylamino) aliphatic acid 18 is formed, which on warming with acetic acid results in partial deamidation with formation of the corresponding dehydropeptide 19. 

Of the three aromatic DHAs, APhe, ATyr, and ATrp, APhe is the most frequently used and well studied. The main synthetic strategy used to prepare APhe is through the azlactone method. 1,2 Most of the methods to prepare azlactones of APhe have already been discussed (vide supra). The Z-isomer of APhe is obtained by these methods, whereas the E-isomer is prepared by special methods 134 namely by isomerization of the Z-isomer in saturated HBr, 135-137 by photochemical isomerization/138 or from 2-phenyloxazolinonium perchlorate/139 ... 

Cyclization of a-(acylamino)acrylohydrazides (684) with sodium hydroxide or acetic acid/acetic anhydride is the most commonly used method for preparing l,2,4-triazin-6-ones (685) <78HC(33)189, p.258). But since the acrylohydrazides (684) are usually made by hydrazinolysis of azlactones (c/. also 586 -> 588, Section 2.19.4.1.4), this method can also be treated as a [4+2] atom fragment method. 

The azlactone formed from benzo[6]thiophene-2-carboxaldehyde and hippuric acid reacts with hydriodic acid and red phosphorus to give a-amino-/9-(2-benzo[6]tbienyl)propionic acid, and with sodium hydroxide to give a-benzamido-j8-(2-benzo[6]thienyl)acrylic acid.477 A series of a-amino-j8-(5-substituted-3-benzo[6]thienyl)propionic acids (312 R = H) has been prepared by hydrolysis of the product of... 

Protected amino acids with either a free amino or carboxyl function can usually be prepared by proven methods or are even commercially available. Therefore stages (i) - (iii) may be considered as simple routine nowadays, although great care must be taken that the protected starting materials are pure enantiomers. The reactions that cause most trouble are in stages (iv), (v) and (vii). In these stages an activated carboxyl group is involved and the chiral centre adjacent to it is at peril from racemization. A typical reaction which causes epimerization is azlactone formation. With acids or bases these cyclization products may reversibly enolize and racemize. Direct racemization of amino acids has also been observed. 

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