Control of regiochemistry

A successful approach to regiocontrol in the aqueous Diels-Alder reaction using cyclodextrins was reported by Chung and Wang [37]. They found that, while the cycloaddition of 2-methyl-1,4-benzoquinone (3.5) and ( )-l,3-pentadiene (3.6) proceeded about an order of magnitude faster in water than in acetone, essentially the same modest level (ca. 2/1) of regioselection was observed in both  

Significantly, when this same aqueous Diels-Alder reaction was run in the presence of P-cyclodextrin, the regioselectivity favoring the ortho adduct 3.7 increased to ca. 5/1. An even more dramatic effect is seen with 3.5 and 2-methyl-1,3-butadiene (3.9). With this less reactive diene, the cycloadditions in both acetone and water are inefficient (low yielding) and relatively nonselec-ti e( paraTmeta ca. 1/1)  

However, a reversal of regioselectivity, now favoring the meta adduct 

was observed when the aqueous reaction was conducted in the presence of P-cyclodextrin. These examples of cyclodextrin-mediated regiocontrol are likely related to a favored transition-state geometry (a preorganizational effect) within the hydrophobic binding cavity. 

Jaeger and co-workers have reported the results of experiments which demonstrate that expected orientational effects in micelles or related aggregates cannot always be counted upon to override the intrinsic FMO regiocontrol of the Diels-Alder reaction [38]. Thus, the surfactant diene 3.12 reacted with a four-fold excess of (non-orientational) dienophile 3.13a (R = H) in water to give a mixture of ortho adducts 3.14a/3.15a in 93% combined yield  

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Control of Regiochemistry and Stereochemistry of Mixed Aldol Reactions of Aliphatic Aldehydes and Ketones... 

A major challenge in the chemistry of dienolates is the control of regiochemistry. A number of factors determine the final regiochemical outcome (a v.s attack) of the reaction between 190 and an electrophile E+ (equation 97). 

Utilization of an oxygen nucleophile gives similar results (Scheme 8E.35). Whereas modest enantioselectivities (7-54% ee) have been recorded with various ligands [177], the use of 5 results in the efficient cyclization of phenol to furnish the nucleus of tocopherol (vitamin E) with 86% ee [178], Extension of this methodology to intermolecular reactions requires control of regiochemistry, a problem that is not present in the corresponding intramolecular... 

The control of regiochemistry has been rationalized on the basis of the orbital coefficients of the HOMOs and LUMOs, but in fact, it is not well understood. In most cases such cycloadditions are not regiospecific and isomeric mixtures are formed, although one regioisomer usually predominates. Qualitative estimation of the electron distributions in the diene and dienophile can often be used to predict the major product. For example, C-l of siloxy diene (A) should be much more electron rich than C-4. In addition C-3 of acrylate (B) should be more electron deficient than C-2. 

Fig. 6. Controlling stereochemistry and regiochemistry in Diels-Alder reactions by the application of very high pressure. The potential for using elevated pressures to obtain asymmetric induction is based upon exploiting the different volumes of activation between the competing diastereoisomeric transition states [48, 54]. In the first example, a AAV of 0.9 cm3 mol-1 favors the formation of diastereoisomer 15 over diastereoisomer 16 as the pressure is increased. In the second example, the increased ratio of 18 relative to 17 illustrates the importance of pressure variations in the control of regiochemistry...

Despite these modifications, Ireland s original method of both vinyl phosphate formation and reduction remains the most popular. In studies on the cationic rearrangements of [4.3.2]propellanes, Smith et converted a tricyclic ketone, via the diethyl vinylphosphate derivative, into the corresponding alkene (Scheme 26). In a similar manner, Kamata et al prepared A - and A -steroids (Scheme 27) with excellent control of regiochemistry. As shown in this example, esters are susceptible to cleavage under the standard reduction conditions (Li, NHa, Bu OH, -35 C), while acetals survive. 

Control of regiochemistry is a serious problem in the addition to unsymmetrical alkenes. Some regioselectivity can be obtained by the use of alkenes attached to an... 

Reductive coupling of alkynes or alkenes may be carried out with Cp2ZrCl2, Ti(0-i-Pr)4, or other Ti(IV) and Zr(IV) complexes. The reaction is often carried out in an intramolecular fashion to achieve better control of regiochemistry. The diyne or other polyunsaturated compound is added to a mixture of the Zr(IV) or Ti(IV) complex and a reducing agent such as BuLi. After formation of the intermediate metallacycle, the C-M bonds are cleaved by treatment with an electrophile such as H+ or I2 to give the organic product. 

In organic chemistry, allylic substrates are relatively reactive toward some nucleophiles, as shown in equation 12.25. The reaction suffers, however, from a number of disadvantages, including unpredictable stereochemistry, poor control of regiochemistry, and the possibility of carbon-skeleton rearrangements. 

Control of regiochemistry of radical cyclizations in the synthesis of physiologically active /V-heterocycles 04YGK325. 

This hydrocarboration method is a valuable tool in industrial and laboratory synthesis, since it allows introduction of the one-carbon unit of carbon monoxide into unsaturated substrates and construction of new carbon skeletons with aldehyde functions or derivatives thereof formed by reduction, oxidation, condensation and other conversions. Hydroformylation, mainly catalyzed by cobalt, rhodium, or platinum complexes is an unsymmetrical 1,2-addition leading to linear and branched products if terminal olefins are used as the substrate. Since linear products are normally the industrial products wanted54, considerable efforts have concentrated on the control of regiochemistry. Other problems of the hydroformylation method arise from side reactions such as hydrogenation, double bond migration, and subsequent reactions of the products (e.g., condensation, reduction, dccarbonylation)54. 

The wide synthetic applicability of the aldol reaction depends on the ability to achieve both versatility in reactants and control of regiochemistry and stereochemistry. The term directed aldol additiori is applied to reaction conditions that are designed to achieve specific regio- and stereochemical outcomes. Control of product structure requires that one reactant act exclusively as the electrophile and the other exclusively... 

Chapters 4 to 7 review the basic substitution, addition, and elimination mechanisms, as well as the fundamental chemistry of carbonyl compounds, including enols and enolates. A section on of the control of regiochemistry and stereo- chemistry of aldol reactions has been added to introduce the basic concepts of this important area. A more complete treatment, with emphasis on synthetic applications, is given in Chapter 2 of Part B. 

Figure 11.10. Frontier orbital control of regiochemistry for electron-rich dienes and acrolein.

More recently, Bagley and coworkers prepared tri or tetrasubstituted pyridines by microwave irradiation of ethyl j5-aminocrotonate and a variety of alkynones in a single synthetic step and with total control of regiochemistry (Scheme 10.25) [60]. 

Deaza-5,8-dihydropterins were prepared from 2,6-diaminopyrimidin-4-one, 1,3-dicarbonyl compounds, or benzoylacetonitrile, and aromatic or aliphatic aldehydes [115]. This three-component cyclocondensation proceeds under microwave-assisted conditions in good yield using Zn(II) bromide as a Lewis acid catalyst, and with total control of regiochemistry. 

Another way of forming more complex, nonsymmetrical DHPs was introduced by Bagley et al. [36]. The authors developed a one-pot three-component cyclocondensation reaction for preparation of 5-deaza-5,8 dihydropterin 6 (Scheme 17.7) which proceeded with total control of regiochemistry [37]. The three-component reaction was originally conducted under thermal conditions and was catalyzed by zinc(II) bromide but required long reaction times and quite high temperatures to obtain a good yield of the cyclized product 6. 

Scheme 4 Control of regiochemistry by metal catalyst in hydrophosphinylation polymerization of diynes...

Diazonium salts are discussed on p. 520. Chapter 40 introduces the idea of using transition metals in the formation of bonds to aromatic rings, while Chapter 24 revisits the methods available when control of regiochemistry (i.e. ortho, meta, or para selectivity) is needed. 

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