A,/3-unsaturated acids esters

Reactions of this type provide major routes to both the monocyclic system and to 1,5-benzothiazepines. In some cases the reactions are single-stage processes but in many cases the intermediate produced by the primary formation of the S—C bond can be isolated. Thus 2-aminoethanethiol reacts with a,/3-unsaturated or j3-halogeno ketones to give (408). Similarly reaction with a,/3-unsaturated acids, esters or acid chlorides and with 3-halogenopropionyl halides gives the 5-oxo derivative (409). 2-Aminoethanethiol also reacts with activated 2-chlorobenzophenones to give 1,4-benzothiazepines. 

Aminoethanethiol reacts with ot, 3-unsaturated or (3-halo ketones to give (355). Similarly, reaction with a, (3-unsaturated acids, esters or acid chlorides, and with 3-halopropionyl halides, yields 5-oxo derivatives such as (356). Thioglycollic acid (HSCH2C02H) with 3-bromopropylamine gives (357). 

This catalyst is useful for selective reduction of the carbon-carbon double bond of a,/3-unsaturated acids, esters, ketones, nitriles, and nitro compounds. Sterically hindered double bonds, however, are not reduced. Selective hydrogenation of a,j8-unsaturated aldehydes is hampered by concomitant decarbonylation this reaction can be suppressed to some extent by carrying out the hydrogenation in absolute ethanol. The hydrogenations were conducted in benzene or ethanol at 40-60° and 60-100 psi pressure for 12-18 hours.5... 

More typical behavior of ketones is a condensation process yielding p-acylamino ketones. This process was first reported by Bruson et al who reacted cyclohexanone and nitriles in the presence of anhydrous aluminum chloride and obtained products now known to have the structure (35). Such reactions were later studied in more detail by Khorlin using conventional Ritter conditions. 3-Acylamino ketones were obtained only from ketones capable of undergoing condensations to produce a,3-unsaturated ketones or ketols, suggesting the intermediacy of such structures in the reaction. This process is shown for acetophenone in Scheme 14. It is well established that a, 3 unsaturated acids, esters and ketones yield similar products under Ritter reaction conditions. - ... 

Addition of sodium enol malonates to a,)3-unsaturated acid esters (Michael condensation). 

Treatment of [2- C]malonic acid with acetone in the presence of acetic anhydride and catalytic amounts of concentrated sulfuric acids provides [5- C]Meldrum s acid (419). one of the most versatile low molecular weight building blocks . As summarized in Figure 6.124, its reactivity at C2 is analogous with that of the malonate diesters already discussed. However, the reactivity of the initial adducts differs. For example, hydrolysis or alcoholysis (including tert-BuOH) of the initial adducts with alkyl halides , aldehydes and acyl chlorides gives directly the [2- C]carboxylic acids/esters, a,/3-unsaturated acids/esters and /3-keto acids/esters, respectively, with simultaneous elimination of acetone and In contrast, the 2-(alkoxymethylene)[2- C]malonate... 

The unified highly convergent total and formal syntheses of ( + )-macro-sphelides B (441 X = O) and A (441 X = a-OH, p-H), respectively, have been described (483). Key features of the syntheses include the concise synthesis of the optically active S-hydroxy-y-keto a, 3-unsaturated acid fragment 442 via the direct addition of a fra/i.s-vinylogous ester anion equivalent to a readily available Weinreb amide, and the facile construction of the 16-membered macrolide core of the macrosphelide series via an INOC. 

A naphthalene-catalyzed (<10%) lithiation of a,a-dibromo esters 152 in THF at —78°C was used to generate ester dianions 153, which by warming at 0°C gave lithium ynolates 154. These intermediates were trapped by carbonyl compounds, for instance benzophenone, to give, after final hydrolysis with water, a,/3-unsaturated acids 155 (Scheme 55)" ... 

Pyrazolinones and isoxazolinones are prepared from (3-keto esters and hydrazine or hydroxylamine by reactions such as (34 — 35) similar to those in (i) above. Diketene behaves as a masked (3-keto ester. Acetylenecarboxylic esters can be used in place of (3-keto esters to give pyrazolinones such as (36) and (37) and the corresponding isoxazolinones. (3-Chloro-a,(3-unsaturated acid chlorides react similarly (cf. 38 — 39). 

Sulfanylalkanoyl amino acids and peptides are prepared by reaction of the (acetyl-sulfanyl)- or (benzoylsulfanyl)alkanoic acids or acid chlorides with a-amino esters or peptide esters, followed by deprotection of the sulfanyl and carboxy groups. 8 101114 16 27 29 For example, the 3-(acetylsulfanyl)alkanoic acids 7 are prepared from the condensation of ethyl (diethoxyphosphoryl) acetate 5 with various aldehydes according to the Horner-Emmons reaction, providing the a, 3-unsaturated ethyl esters 6 (a mixture of Z- and E-isomers, 50 50), followed by saponification of the ethyl esters and Michael addition of thiolacetic acid. The 3-(acetylsulfanyl)alkanoic acids 7 can be coupled with a-amino esters or peptide esters and subsequent hydrolysis of the 3-(acetylsulfanyl) derivatives provides the desired products 8 (Scheme 2). 14 ... 

A large part of the usefulness of the Michael reaction in organic synthesis derives from the fact that almost any activated alkene can serve as an acceptor7—a, 3-unsaturated ketones, esters, aldehydes, amides, acids, lactones, nitriles, sulfoxides, sulfones, nitro compounds, phosphonates, phosphoranes, quinones,... 

Palladium acetate triarylphosphine complexes catalyze the addition of vinylic groups from vinylic halides to olefinic compounds in the presence of amines. Conjugated dienes are major products from 0,/3-unsaturated acids, esters, or nitriles while unactivated olefinic compounds react best in the presence of secondary amines where allylic amines are major products. The reactions are usually regio- and stereospecific. The synthetic utility of the reaction is illustrated with a wide variety of examples. 

RCu-BF3 (8,334-335 9,333). Yamamoto etal.,15 have reviewed and extended their research on the RCu-BF3 system. This system is superior to R2CuLi for conjugate addition to sterically hindered a,/(-unsaturated ketones and esters, but is less useful in reactions with a,/3-unsaturated acids and is unsatisfactory for additions to a,/l-unsaturated nitriles. A typical example is formulated in equation (I). 

Synthesis of substituted acetic acids via acetoacetic ester... 146 Synthesis of substituted acetic acid via malonic ester. .. 150 a halo acids, a hydroxy acids, and a, (3 unsaturated acids.. .153... 

The C—C(=0)—O band of saturated esters, except for acetates, shows strongly in the 1210-1163 cm"1 region. It is often broader and stronger than the C=0 stretch absorption. Acetates of saturated alcohols display this band at 1240 cm"1. Vinyl and phenyl acetates absorb at a somewhat lower frequency, 1190-1140 cm"1 for example, see Figure 2.25. The C—C(=0)—O stretch of esters of a,/3-unsaturated acids results in multiple bands in the 1300-1160 cm"1 region. Esters of aromatic acids absorb strongly in the 1310-1250 cm"1 region. 

Kochetkov and Dmitriev have reported66,79 an investigation on the hydroxylation of certain a,)3-unsaturated aldonic esters. The hydrox-ylation was performed by treatment of these compounds with chloric or iodic acid (or their salts) and a catalytic amount of osmium tetra-oxide in a suitable solvent. The resulting diastereoisomers were then separated as their cadmium salts. 

A recent example of zeolite-catalyzed esterification involving biochemicals is the reaction of aminoacids with methanol. For instance, L-phenylalanine was converted to its methyl ester over H-USY at 130°C. However, the chiral carbon atom was racemized to a considerable extent, yielding an eventual ee of 52% (27). In the reaction of a, (3-unsaturated acids with phenols, the esterification over H-Beta is followed by an alkylation of the aromatic ring for instance resorcinol and acrylic acid react to form 7-hydroxy-3,4-dihydrocoumarin (28). 

In the carbonyl region, at a weak extent of conversion, photooxidation of ABS and BR led to the formation of a thin absorption band with maxima at 1697 cm-1 (a, (3-unsaturated acids) and 1683 cm-1 (a, (3-unsaturated ketone), and to the formation of a broader absorption band with a maximum at 1721 cm-1. As photooxidation proceeded, the intensity of this latter band increased and shifted to 1717 cm-1 whilst the band at 1697 cm-1 became hard to observe. The intensity of the band at 1697 cm-1 ceased to increase after 16 h of irradiation. When the exposure time was longer than 22 h, only one absorption band was observed. Its maximum shifted from 1717 to 1725 cm-1. In parallel, a shoulder was detected in the range 1775-1785 cm-1. It was shown that the absorption around 1725 cm-1 resulted from the convolution of various species saturated carboxylic acid (1717 cm - ), aliphatic ester (1735 cm-1), a, (3-unsatur-ated anhydride (1724-1782 cm-1), saturated aldehyde (1727-2720 cm-1) and saturated ketone (1725 cm-1). The maximum at 1780 cm-1 has been assigned to three types of structure a, (3-unsaturated anhydride (1724 and 1782 cm-1), perester (1789 cm-1) and 7-lactone (1775 and 1175 cm-1). 

Conjugate addition of a silylcuprate reagent (34) to the a,(3-unsaturated acid amide or ester of a pertinent chiral amine or alcohol, respectively, is an alternative route to (3-silyl amides and esters. Conjugate addition of a cuprate reagent to a P-silyl acrylamide also gives a chiral P-silyl amide. The diastereomeric excess of the newly produced chiral center is fairly high, as summarized in Scheme 14." ... 

A number of syntheses of 2-pyrazolin-5-ones depend on the reaction of compounds, other than /3-ketoesters, substituted in the /3-position or of a,/8-unsaturated acids, esters and amides. The most frequently used unsaturated compounds are those having a triple bond in the apposition.1023,1024,1075,1548,1680 R2 can be HO,1552 RO1023,1024,1686 or H2N (eq. 8).1023,1024 A similar reaction is the condensation of ethyl... 

A library of chiral dihydropyrans (226) [241] was synthesized using asymmetric hetero-Diels-Alder reactions (HAD) on polymer-bound enol ethers (221) and a, 3-unsaturated oxalyl esters (222). A chiral Lewis acidic Cu -bisoxazoline complex was used because of its high efficiency, the high predictability of the reaction outcome, and its broad substrate tolerance [280]. Enol ethers were used as alkene components bearing a hydroxy function for attachment to the resin via a silyl linkage (Scheme 49). The diene components carried allyl-ester groups, which could be readily displaced by amino functions in subsequent steps of the combinatorial synthesis. 

Although, in both cases, the polyglycosiduronic acids are more stable than their esters, they are not completely stable to alkaline solutions. For example, 43% of the glycosidic bonds in 4-0-(i8-D-glucopyranosyluronic acid)-D-glucaric acid are cleaved in 20 min. with 0.1 A sodium hydroxide at 20°. Some instability would be expected because of the well-known formation of a,(3-unsaturated acids from /3-hydroxy acids. 3-0-Substituted... 

Other atropisomeric phosphines 3.45 have been recommended as ligands in rhodium-catalyzed asymmetric hydrogenations of prochiral a,[3-unsaturated acids or esters [892, 904] when R = c-CgHj or in rhodium-catalyzed asymmetric isomerization of allylamines 3.44 [905] when R = Ph. These phosphines 3.45 (R = Ph or c- CgHj j) are interesting ruthenium ligands in asymmetric hydrogena-... 

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