Thermodynamic control regiochemistry

Conra.d-Limpa.ch-KnorrSynthesis. When a P-keto ester is the carbonyl component of these pathways, two products are possible, and the regiochemistry can be optimized. Aniline reacts with ethyl acetoacetate below 100°C to form 3-anilinocrotonate (14), which is converted to 4-hydroxy-2-methylquinoline [607-67-0] by placing it in a preheated environment at 250°C. If the initial reaction takes place at 160°C, acetoacetanilide (15) forms and can be cyclized with concentrated sulfuric acid to 2-hydroxy-4-methylquinoline [607-66-9] (49). This example of kinetic vs thermodynamic control has been employed in the synthesis of many quinoline derivatives. They are useful as intermediates for the synthesis of chemotherapeutic agents (see Chemotherapeuticsanticancer). 

Scheme 2.11 shows some examples of Robinson annulation reactions. Entries 1 and 2 show annulation reactions of relatively acidic dicarbonyl compounds. Entry 3 is an example of use of 4-(trimethylammonio)-2-butanone as a precursor of methyl vinyl ketone. This compound generates methyl vinyl ketone in situ by (3-eliminalion. The original conditions developed for the Robinson annulation reaction are such that the ketone enolate composition is under thermodynamic control. This usually results in the formation of product from the more stable enolate, as in Entry 3. The C(l) enolate is preferred because of the conjugation with the aromatic ring. For monosubstituted cyclohexanones, the cyclization usually occurs at the more-substituted position in hydroxylic solvents. The alternative regiochemistry can be achieved by using an enamine. Entry 4 is an example. As discussed in Section 1.9, the less-substituted enamine is favored, so addition occurs at the less-substituted position. 

The reaction proceeds via electrogenerated cationic species as its seen with the nonfluorinated amines, carbamates, and amides (Scheme 6.14). However, the regiochemistry of this anodic methoxylation is not governed by the stability of the cationic intermediates B and B (thermodynamic control) since the main products are formed via the less stable intermediates B. Indeed, this remarkable promotion effect and unique regioselectivity can be explained mainly in terms of a-CH kinetic acidities of the cation radicals formed by one-electron oxidation of the amines since the stronger the acidity of the methylene hydrogen, the easier the deprotonation. 

The regiochemistry of the addition depends on temperature and solvent. At low temperatures, under kinetic control, the AM products are favored while at room temperature or above, under thermodynamic control, the M adducts are generally formed. 

However, the reaction of 1,3-cycloheptadiene is less regioselective. Isoprene and E,E-2,4-hexadiene afford 1,2-/1,4-adducts in ratios of 87 13 and 83 17, respectively. The high selectivity for 1,2-addition (>95%) to 1,3-pentadiene is opposite to the corresponding oxymercuration of the same diene, which has been reported159 to give mainly 1,4-adducts. The different regiochemistry has therefore been explained by assuming that sulfomercu-ration occurs under kinetic control whereas oxymercuration occurs under thermodynamic control. 

However, the syn and anti isomers of imines are easily thermally equilibrated. They cannot be prepared as single stereoisomers directly from ketones and amines so this method cannot be used to control regiochemistry of deprotonation. By allowing lithiated ketimines to come to room temperature, the thermodynamic composition is established. The most stable structures are those shown below, which in each case represent the less substituted isomer. 

However, orbital factors may override thermodynamic control. For example, the regiochemistry of nucleophilic attack on the bridged norcaradiene radical cation 122 shows a significant deviation from thermodynamic control. Although attack on the cyclopropane ring should be favored by both release of ring strain and formation of delocalized free radicals (cf. Scheme 6.8), methanol attacks 122 " selectively at C2 (and C5), generating 123 and 124. There is little stereoselectivity Products derived from 123 and 124 were formed in comparable yields. ... 

While the regiochemistry of simple electrophilic additions to double bonds is controlled by a combination of electronic (Maikovnikov rule), stereoelectronic (trans diaxial addition to cyclohexenes) and steric factors,9 the intramolecular nature of electrophilic heteroatom cyclizations introduces additional conformational, stereoelectronic and entropic factors. The combination of these factors in cyclofunctionalization reactions results in a general preference for exo cyclization over endo cyclization (Scheme 4).310 However, endo closure may predominate in cases where electronic or ring strain factors strongly favor that mode of cyclization. The observed regiochemistry may differ under conditions of kinetic control from that observed under conditions of thermodynamic control. 

Tuning of selectivity in the metallation of m-anisic acid has been realized by an appropriate choice of base.67 The results obtained with LTMP have indicated that the regiochemistry of the lithiation of m-anisic acid is thermodynamically controlled. Resonance and inductive effects favour removal of the H(2) proton. In contrast, superbases such as n-BuLi-r-BuOK are not significantly influenced by or//m-directing groups and preferentially attack H(4), the inductively activated aromatic position next to the most electronegative heteroatom and/or the most acidic position available. 

Selenenyl chlorides add to alkenes, often via an AdE2 mechanism involving a bridged seleniranium ion intermediate (19) (equation 14). These reactions are therefore highly stereospecitic, resulting in anti addition. The regiochemistry of the process can be under either kinetic or thermodynamic control. In some cases, initial anti-Markovnikov products were observed at low temperature and Markovnikov adducts dominated after further equilibration. Analogous electrophilic additions to acetylenes and aUenes (Scheme 9) have also been reported. When selenenyl hahdes react with alkenes in the presence of other nucleophiles such... 

Other radicals can add to alkenes, and the rate constant for the addition of methyl radicals to alkenes has been studied,and the rate of radical additions to alkenes in general has also been studied.The kinetic and thermodynamic control of a radical addition regiochemistry has also been studied. Alkynes... 

The nature of the base can profoundly influence the regiochemistry of the reaction. f-BuOK favors kinetic control in the reaction shown in eq 16 and the product derived from cyclization of the enolate having a /3-amino group is obtained. However, when EtONa/EtOH is employed, the more stable /3-keto ester enolate resulting from thermodynamic control is obtained. In addition to diesters, dinitriles, e-keto esters, e-cyano esters, e-sulfinyl esters, and -phosphonium esters may participate in these reactions. 

The influence of two meto-interrelated DMGs can be concerted to direct the metalation in between them. LTMP metalates meta-znmc acid 9 in THF at 0°C at the doubly activated position (C2) [62]. The regiochemistry of this lithiation is truly thermodynamically controlled resonance and inductive effects favor removal of the H2 proton. LICKOR deprotonates preferentially the C4 position. To prepare 6-substituted benzoates, one has to (i) protect the C2 site by introducing a trimeth-ylsilyl group with LTMP, (ii) lithiate with s-BuLi/TMEDA, (iii) quench with an electrophile, and (iv) remove the protecting group in C2. 

Although problems of regiochemistry are inherent, the aldol condensation of diketones has found vide application. Typical examples are syntheses of cyclopentenones and cyclohexenones from 1,4- and 1,5-diketones, respectively. The concept is illustrated by a synthesis of jasmone 12 (Eq. (12)) [28] and of the homosteroid derivative 13, the latter arising under thermodynamic control in a Robinson annelation reaction (Eq. (13)) [29]. 

As an approach to biomimetic catalysis, Sanders and colleagues [67] synthesized a series of 1,1,2-linked cyclic porphyrin trimers that allow the stereo- and regiochemistry of the Diels-Alder reaction of 84 and 85 within the molecular cavity to be controlled, thereby producing prevalently or exclusively the endo 86 or the exo 87 adduct. Two examples are illustrated in Scheme 4.18. At 30 °C and in the absence of 88, the reaction furnishes a mixture of diastereoisomers, while the addition of one equivalent of trimer 88 accelerates the reaction 1000-fold and the thermodynamically more stable exo adduct 87 is the sole detectable product. 

The regiochemistry of the acid-catalyzed water addition to cis- (8c) and trans- (8t) 1-ethoxy-l,3-butadienes leading to 9c and 9t, respectively33, has been investigated in deuterium incorporation experiments (equations 5 and 6). The c/s-isomer incorporated deuterium at the 2-position as well as the 4-position whereas deuterium was added to the fraws-isomer exclusively at the 4-position. This result has been interpreted in terms of equations 7 and 8 y-protonation in the frans-isomer was assumed to be controlled mainly by thermodynamic factors whereas a-protonation was assumed to arise from charge control... 

The reaction has been incorporated into a synthetic approach to enediynes [77]. Structural and mechanistic studies by Oehlschlager established the reversibility of these stannylcupration reactions [25cj. Although the resultant vinylcopper reagents were thermodynamically favored, crossover experiments found facile ligand exchange processes. Efforts to control the regiochemistry of the addition were met... 

Regiocontrol Although Michael additions to [Os]-phenol occur selectively at C4, addition at C2 is thermodynamically favored for phenol complexes that are substituted at C4. For C4-substituted phenol complexes, the regiochemistry can be controlled by varying the time, temperature, and catalyst (Figure 6) [29]. Additions of MVK to the estradiol complex 90 and the p-cresol 94 at —40 °C in the presence of an amine base catalyst result in regioselective C4 alkylation in high yields (91 and 95). However, when this reaction is performed at room temperature in the presence of a Zn2+ co-catalyst, the Michael acceptor adds at C2 to afford... 

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