Synthetic equivalents enamines

When pyrimidinone 3 is treated with ethyl 3-oxobutanoate 19a in the presence of ammonium acetate, a different type of TCRT proceeds, giving ethyl 4-aminopyridine-3-carboxylate 41a (Table 10) [59]. In this reaction, pyrimidinone 3 behaves as the synthetic equivalent of activated diformylamine 5, and the amino group at the 4-position is derived from ammonium acetate. Since 3-ethoxycarbonyl-4-pyridone 14a prepared in Sect. 5.2 is intact under the same conditions, aminopyridine 41a is not formed via pyridone 14a. Furthermore, ammonium ion also causes no change on ethyl 3-oxobutanoate 19a, which indicates enamine is not dinucleophilic reagent in the present reaction. Hence, the keto ester moiety is converted to the enaminone after the addition of 19a to pyrimidinone 3. 

The enol content of simple ketones is much lower than that of /1-ketoesters or /3-diketones. For a number of electrophiles it is often too low. Hence, functionalizations with the respective electrophile via the enol form do not succeed in these cases. This problem can be managed, though, by converting the ketone (Formula A in Figure 12.16) into an enamine D with the aid of a condensation with a secondary amine that is in line with Figure 9.29 and the mechanism given there. Enamines are common synthetic equivalents for ketonic and aldehyde enols. 

According to Section 12.3 enamines are just one synthetic equivalent for enols that are not sufficiently represented in equilibrium with a carhonyl compound to allow for a-functional-izations. Enol ethers and silyl enol ethers, which are addressed in this section, are other synthetic equivalents for such enols. An enol ether, for example, is used as an enol equivalent for aldehyde enols, since several aldehydes do not form stable enamines. In addition, enol ethers or silyl enol ethers are usually employed as synthetic equivalents for the enols of ,/i-unsatu-rated carbonyl compounds. The attempt to react ce,/ -unsaturated carhonyl compounds with secondary amines to give a dienamine is often frustrated by a competing 1,4-addition of the amine. The combination of these factors turns the dienol ether B of Figure 12.23 into a species for which there is no analog in enamine chemistry. 

The reverse aldol reaction is catalyzed by an enzyme called aldolase. One of the roles of the enzyme is to stabilize the enolate anion intermediate because such ions are too basic to be produced under physiological conditions. In animals, aldolase accomplishes this task by forming an inline bond between the carbonyl group of fructose-1,6-bisphosphate and the amino group of a lysine amino acid of the enzyme. As a result, the product of the reverse aldol step is an enamine derived from DHAP rather than its enolate anion. (Section 20.8 shows that enamines are the synthetic equivalents of enolate anions.) The formation of the strongly basic enolate anion is avoided. This process is outlined here ... 

After the enamine has been used as a nucleophile, it can easily be hydrolyzed back to the ketone and the secondary amine by treatment with aqueous acid. This is simply the reverse of the process used to prepare it. Overall, enamines serve as the synthetic equivalent of ketone enolate anions. Examples are provided in the following equations ... 

Enamines may be regarded as synthetic equivalents of enolate ions and are closely related to the enolates derived from ketones in their reactions with acyl halides, alkyl halides and a,3-unsaturated compounds. 

In the synthesis described in Scheme 10.10, the stereochemistry is established at an early stage. Stereoselectivity in the protonation of the enamine moiety during the hydrolysis in step B is presumably the result of preferential protonation from the less hindered side of the molecule. None of the other transformations affects these chiral centers, and the overall synthesis is stereoselective. It is interesting to note that step E in this synthesis employs a protected cyanohydrin as a nucleophilic acyl synthetic equivalent. 

The nucieophiiicity of the carbon of enamines makes them particularly useful reagents in organic synthesis because they can be acylated, alkylated, and used in Michael additions (see Section 19.7A). Enamines can be used as synthetic equivalents of aldehyde or ketone enolates because the alkene carbon of an enamine reacts the same way as does the a carbon of an aldehyde or ketone enolate and, after hydrolysis, the products are the same. Development of these techniques originated with the work of Gilbert Stork of Columbia University, and in his honor they have come to be known as Stoik enamine teactions. 

Ordinary enolates are very reactive (strong nucleophiles and strong bases) and can give mixtures of 1,2- and 1,4-addition reactions with a,P-unsaturated carbonyl compounds. The Michael reaction requires a softer enolate, such as a stabilized enolate with two EWGs. Otherwise, an enamine can be used as the synthetic equivalent of an enolate (followed by hydrolysis to regenerate the carbonyl). 

Enamines (which are synthetically equivalent to enolate anions). 

The Pd-catalyzed Claisen rearrangement of allyl vinyl ethers to give a-allylated carbonyl compounds is a synthetic equivalent to those allylation reactions of enolates, enamines, and imines discussed in Sects. B and C.i as well as to the Tsuj-Trost reaction discussed in other sections. Although it is mostly discussed in Part IX as a rearrangement reaction. 

Retro-aldol disconnection of a,P-unsaturated ketone leads to 1,4-diketone TM 5.19a. By disconnection of the central C-C bond, we generate two synthons, a-carbanion of cyclohexanone and a-carbocation in acetone. Synthetic equivalents for two synthons are the enamine of cyclohexanone TM 5.19b and a-chloroacetone TM 5.19c (Scheme 5.45). 

Enamines are the synthetic equivalents of aldehyde and ketone enolates. 

An a-brominated carbonyl compound is the synthetic equivalent for the positively charged a-carbon and an enamine is the synthetic equivalent for the negatively charged a-carbon. An enamine avoids the requirement for a strong base that could remove a proton from the brominated carbonyl compound rather than from the nonbrominated carbonyl carbon. Because esters cannot form enamines, path A is the preferred disconnection. Fortunately, the iminium ion hydrolyzes more readily than the ester. 

An a,jS-unsaturated carbonyl compound is the synthetic equivalent of a compound with a positively charged j8-carbon. And we have seen that an enamine is the synthetic equivalent for the negatively charged a-carbon. 

PROBLEM 7 Because the target molecule is a 1,5-dioxygenated compound, it can be synthesized from a negatively charged a-carbon (using an enamine as the synthetic equivalent) and an a,j8-unsaturated ketone. 

The first section of this chapter describes the preparation and several synthetic applications of a-fluoroalkyl P-sulfmyl enamines and imines the second deals with the chemistry of di- and trifluoropyruvaldehyde A, 5-ketals, stereochemically stable synthetic equivalents of P-di and P-trifluoro a-amino aldehydes, which can be prepared from the corresponding p-sulfinyl enamines the third overviews the preparation of chiral sulfinimines of trifluoropyruvate and their use to prepare a library of a-trifluoromethyl (Tfm) a-amino acids the fourth section is mainly dedicated to the asymmetric synthesis of monofluorinated amino compounds, using a miscellany of methods such as MifstmobuAike azidation of P-hydroxy sulfoxides, ring opening of fluoroalkyl epoxides with nitrogen-centered nucleophiles and 1,3-dipolar cycloadditions with chiral fluorinated dipolarophiles. 

The synthetic application of reactions based upon the intramolecular addition of a carbanion or its enamine equivalent to a carbonyl or nitrile group has been explored extensively. One class of such reactions, namely the Dieckman, has already been discussed in Section 3.03.2.2, since ring closure can often occur so as to form either the C(2)—C(3) or C(3)—C(4) bond of the heterocyclic ring. Some illustrative examples of the application of this type of ring closure are presented in Scheme 46. 

This type of reaction is very common in the nitrogen equivalent pyridine system (the ready formation of enamines and the ready availability of 1,3-electrophiles, such as acrolein and their equivalents). With the phosphorus system, the not so common enamine equivalent makes it a not so common synthetic approach. However, with proper substituents 1,3-dinucleophilic P-C(2) fragments have been reacted with 1,3-electrophiles, and have been used in the synthesis of As-phosphinolines <1996CHEC-II(5)639>. 

Benzoquinones reacted with four equivalents of isonitriles to form benzo[c c ]dipyrroles <84LA1003>, and variations of the Nenitzescu reaction, i.e. of quinones with enamines, have been useful synthetic approaches to benzo[l,2-6 4,5-6 ]dipyrroles <71T503J, 73T921). 

Recent research demonstrated that these problems can be circumvented by a simple change of the order of synthetic steps ketones 8 were first transformed to enamines 9 in a conventional manner. The allylic chlorine was then introduced with one equivalent of N-chlorosuccinimide to give chloroenamine 10. While for R R enamines 9 were usually obtained as a mixture of regioisomers, their reaction with A-chlorosuccinimide often... 

The first of these modifications was developed by Stork and co-workers, who explored the synthetic utility of enamines as enolate equivalents (3). One class of electrophiles that react with enamines are electrophilic olefins, a, jS-unsaturated aldehydes, ketones, esters, amides, and nitriles. 

Another synthetically useful carbon bond-forming reaction involves reaction of diiron nonacarbonyl with halo-carbonyl compounds. Noyori found that a,a -dibromoketones (498) react with diiron nonacarbonyl [Fe2(CO)9] to give an iron stabilized alkoxy zwitterion (499). The intermediate Jt-allyl iron species reacts with alkenes in a stepwise manner (initially producing 500) to give cyclic ketones such as 501, 23 and the product is equivalent to the product of a [3-t2]-cycloaddition with an alkene (sec. 11.11). This cyclization method is now known as Noyori annulation. This reaction is related to the Nazarov cyclization previously discussed in Section 12.3.C. Enamines can react with 498, but the initially formed enamino ketone product eliminates the amino group to form cyclopentanone derivatives. Intermediates such as 499 may actually exist as cations hound to a metal rather than as the alkoxide-iron structures shown.323b-d noted that Zn/B(OEt)3 is... 

Enamines.—A new group of versatile synthetic intermediates, /8-lithioenamines (4) and (5), may be prepared in quantitative yield by the treatment of a bromo-enamine with n- or t-butyl-lithium. /8-Lithioenamines react vigorously at low temperature with various electrophiles to yield -substituted enamines/ (Scheme 9). The lithioenamine (4), a /8-acylvinyl anion equivalent, is considered to be... 

Pyrazoles and indazoles are important synthetic units in biologically active compounds and drugs. Glorius et al. reported a Cu(OAc)2 mediates regiospecific preparation of tetrasubstituted pyrazoles from enamines and nitriles. The C(sp )-H bond of imine was cleavaged via elimination of HOAc molecule. Cu(OAc)2 plays the role of the Lewis acid and oxidant. Moreover, an excess amount of nitrile was needed for this reaction [110]. To solve this problem, they report a modified synthetic approach using equivalent amounts of nitriles with an efficient Cu(OAc)2 catalyst system and molecular oxygen as the oxidant [111]. 

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