Enamino acid esters

ScHOLLKOPF et al (360) reacted a-metallated isocyanoacetic ester with aldehydes and ketones in aprotic solvents to form formyl-enamino acid esters (24) via intermediate oxazoline carboxylic acid esters. 

Dehydrodipeptides (35) have also been prepared from free enamino acid esters and cyclized after hydrazinolysis of the protective group (366, 368) giving (37). Condensation with carbonyl compounds makes possible the synthesis of unsymmetrical tetradehydropiperazinediones (36). 

The simplest and most satisfactory method of preparing arylidene-enamino acid esters is the P-elimination from 2-aryl-4-thiazolidinecarbo-xylic acid esters (40) on treatment with silver carbonate 287A). Arylidene-enamino acid N-hydroxysuccinimide esters were prepared and combined with amino acid esters to yield Schiff bases of dehydro-dipeptides. This elimination reaction of thiazolidine carboxylic acid esters has been applied to prepare the extremely unstable benzyUdene dehydroalanine ester, although it was impossible to isolate it. Nevertheless its existence could be proved without a doubt when the reaction was carried out at 0° in trideuterioacetonitrile solution and was followed by NMR spectrometry. Within one half hour at room temperature the unstable substance started to decompose. 

Only a few esters of dehydroamino acids are stable and these only as hydrochlorides, so that all the reactions at the amino group studied to date are electrophilic. As the enamino group is less nucleophilic than an amino group, enamino acid esters can only be acylated by the most reactive acid derivatives, such as acid chlorides (368, 373) and mixed anhydrides (69, 257, 313). Attempted peptide formation from acylamino acids and enamino acid esters by the DCCD or DCCD/hydroxysuccini-mide methods is unsuccessful. The formation of Schiff bases at the enamino group proceeds rather slowly, but can be achieved in the case of the stable dehydrovaline methyl ester by direct condensation with aromatic aldehydes (287, 352). 

The reaction of P-keto acid derivatives and ammonia or amines relies on initial reaction with an aldehyde or ketone moiety. The carbonyl must be P- to the carboxyl group, however, in order to obtain the enamino acid or enamino-ester derivative (an enamine is a "vinyl amine," first used synthetically by Stork, and they are well known). These enamino derivatives are actually 3-aminopropenoic... 

A route to a-enaminocarboxylic acid esters based on N-chlorination/ dehydrochlorination of amino acid esters has been described by H. Poisel and U. Schmidt 312, 313). N-Chlorination of BOC-amino acid esters followed by dehydrochlorination with methoxide affords a-methoxy-a-BOC-amino acid esters (41), which, on treatment with HCl, undergo elimination of methanol and cleavage of the protective group in a single step. The free enamino esters (42) are liberated from their hydrochlorides by treatment with ammonia or triethylamine. NMR spectroscopic studies showed that (42a) and (42c) exist exclusively in the enamino tautomeric form, while (42b) contains about 40% imino tautomer. 

Shin was unable to observe enamino-imino tautomerism in the case of dehydrovaline compounds (253, 373). E. Ohler and U. Schmidt (287, 350) were able to convert a-iminocarboxylic acid esters into a-enaminocarboxylic acid esters (42) by preparing the hydrochlorides of the former, which slowly rearranged into the hydrochlorides of the latter. This reaction is the simplest means of preparing a-enaminocarboxyhc acid esters, as the a-iminocarboxylic acid esters obtained by N-chlorina-tion/dehydrochlorination of amino acid esters can be rearranged directly, without intermediate purification. 

The acylation of enamino ketones can take place on oxygen or on carbon. While reaction at nitrogen is a possibility, the N-acylated products are themselves acylating agents, and further reaction normally takes place. The first reported acylation of enamino ketones (72) was that of 129, prepared by acylation of the enamine (113), which was shown to have undergone O acylation because on mild hydrolysis the enol ester (130) could be isolated. A similar reaction took place with other aliphatic acid chlorides (80) and with dibasic acid chlorides [e.g., with succinyl chloride to give 118 above]. 

General Conditions for each step and selectivity of m-substituted anilines As previously mentioned, Hauser and Reynolds reported on factors governing the first step of the Conrad-Limpach reaction but they tvere by no means exhaustive. Other than the conditions reported above for the first step, HClAleOH, CHCI3 or CHCI2 (neat or with acid catalyst), PhMe or PhH with removal of water with or without acid catalyst, or EtOH/AcOH/CaS04 were reported to provide the desired enamino-ester from an aryl amine and 3-keto-ester. Hauser and Reynolds also noted that o-nitroaniline and o-nitro-p-methoxyaniline failed to form the desired enamino-ester under conditions which they reported. 

The tetracyclic /3-carboline derivatives 452-454 have been prepared as sleep disorder therapeutics. The synthesis (Scheme 100) involves the reaction between the enamino ester 451 and acrylic acid derivatives, activated in certain cases with ethyl chloroformate <1997TL8475>. 

The syntheses of simple 1,3-oxazines (74AG596 86G361) from acylated amino acids (86G361) by treatment with dihalotriphenylphosphorane and of heterocondensed l,3-oxazin-4-ones from several N-acylated heterocyclic /3-enamino esters (81CB3188) have been implemented by aza-Wittig reactions of heterocyclic 2-(triphenylphosphoranylidenamino)esters with acid halides. 

Enamine 106 (derived from Meldrum s acid), in a process of mono-decarboxylating transesterification and subsequent intramolecular alkylation, is cyclized to form enamino ester 107 (90H(31)1251). The direct route by flash vacuum thermolysis does not work in the case of 6/7 bicyclic 107. Methylene compound 109 originates (analogously to bicyclic 40b) from... 

The reactivity of 2-amino-4H-pyrans as well as their chemical properties has been poorly studied because of their weak stability toward many reactants. They undergo ring opening and recyclizations in the presence of strong acids and bases, nucleophiles, and so on. But this feature can be turned to advantage in the synthesis of various heterocycles via recyclizations. Thus, the enamino moiety in 2-amino-4H-pyran-3-carbonitriles and 2-amino-4H-pyran-3-carboxylic esters provides access to diverse derivatives, including fused pyrans. The available data on the chemical properties of 2-aminopyrans are not systematic, and, in certain cases, are contradictory. 

The chemistry used to prepare the antischistosomal hydroxyquinolines provided the initial entry to this series. Thus, addition-elimination of aminopicoline (38-1) to EMME (38-2) gives the corresponding enamino ester (38-3). Thermal cyclization of that intermediate leads to the hydroxyquinoline (38-4). Reaction of the ambident anion from that compound leads to alkylation via the keto tautomer and thus the formation of the Al-alkylated derivative (38-5). Saponification of the ester then gives nalidixic acid (38-6) [44]. It has incidentally been shown that the presence of the strong Michael acceptor function in this series plays a little role in the mechanism of action in these compounds. 

The first representative of this group, a /3-acylamino-a,/8-unsaturated ester, yielded 67 through pyrolysis in diphenyl ether205-207 [Eq. (53)]. A modification of this method used a Schiff s base instead of die TV-acyl derivative of a j8-amino-a,j8-unsaturated acid.208 Similarly, enamino esters react with benzoyl chloride to yield 6//-l,3-oxazines.209... 

Numerous studies of the photoreactions of dihydrofurans have been described. On irradiation 2,3-dihydrofurans are known to undergo conversion to acylcyclopropanes by a pathway involving initial carbon-oxygen bond homolysis. The /i-enamino ester (162), for example, affords the cyclopropane (163) on triplet-sensitized irradiation.138 Similar transformations have been observed in 2,2,4-triacyl-2,3-dihydrofurans,139 and a synthesis of a cis-trans mixture of chrysanthemum carboxylic acid has been accomplished in this way.140 The conversion of the 2-thiazolines(164) to the iV-alkenylthio-amides (165) presumably involves an analogous carbon-sulfur bond homolysis, followed by a 1,2-hydrogen shift in the resulting biradical (166).141... 

This procedure is illustrative of a general method for preparing a wide range of pure 3,5-disubstituted-4-isoxazole-carboxylic esters and (by hydrolysis) their acids,2 free from positional isomers. A wide range of both primary nitro compounds and of enamino esters can be used,2,3 and the esters thus obtained may then be used as reagents in the isoxazole annela-tion reaction.3,4 The only other general synthesis of these compounds involves chloromethylation and oxidation of a suitable 4-unsubstituted isoxazole.5 This procedure suffers from two difficulties low yields and the unavailability of starting isoxazole. Most methods of isoxazole formation yield a... 

Quaternary stereocenters can be obtained with high selectivity with ot-amino acid amides as chiral auxiliaries, which were first converted with P-oxo esters to give enamines such as compounds 58. According to a combinatorial strategy, various enamino esters 58 were screened in Michael additions with MVK (41a) and several metal salts as catalysts. With FeCl3, however, the maximum stereoselectivity achieved was only 77% ee (with enamine 58a derived from L-isoleucine dimethylamide). Cu(0Ac)2H20 turned out be the optimal catalyst for this transformation. With L-valine diethylamide as chiral auxiliary in compound 58b, reaction proceeds with 86% yield and 98% ee after aqueous workup [79]. Importantly, this valuable method for the construction of quaternary stereocenters [80] under ambient conditions seems to be generally applicable to a number of Michael donors [81]. In all cases, the auxiliary can be quantitatively recovered after workup. 

Another remarkable reaction is the methoxymercuration which leads, when applied to derivatives of lysergic acid, to the unique 10-methoxy-A8,9-ergolene derivatives (50) after treatment of the addition product with base and NaBH4 (51). In another recent paper (127) the synthesis of a new structural isomer of lysergic acid methyl ester (28) has been reported in which a novel modification of the Polonovski reaction has been used to introduce the 7,8 double bond. Thus, the A-oxide 51 on treatment with acetic anhydride and excess base, yielded the enamino ester (52) in about 50% yield. 

One of the most widely used methods of synthesizing TAs 16 and 17 is by condensation of thiobenzamides with acetylene mono- and dicarboxylic acids or their esters in methanol. The analogous reaction between en-aminothioamide and acetylene carboxylic acid and its esters leads to enamino-TA 18 (79JAP79 20504) (Scheme 2). 

Extensive use has been made of the enamino ester 494 it reacts with various doubly electrophilic species at the enamine -carbon, and nitrogen, to produce bicyclic products, such as 495 using propiolic acid imidazolide, Scheme 107... 

Tris(organoamino)boranes have been utilized to prepare, in reasonable yields,4,5 mono- and dihalo(organoamino)boranes which are often difficult to obtain by direct amination of the boron trihalides. Carboxylic acids, 1,3-diketones, ketones, and /3-ketoesters have been converted into carboxamides, enamino-ketones, enamines, and j -enamino-amides, respectively, by reaction with an appropriate tris(organoamino)borane under very mild conditions.6 Sulfenamides (R2NSC6H5) have also been prepared in high yield from selected tris(organoamino)boranes and sulfenic esters under relatively mild conditions.7... 

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