Regiochemistry, reversal

Although epoxides, like bromonium ions, contain strained three-membered rings, they require either acid catalysis or a powerful nucleophile to react well. Compare these two reactions of a 1,1,2-trisubs tituted epoxide. They are nucleophilic substitutions related to those we introduced in Chapter 17 (p. 435) but in that chapter we carefully avoided discussing epoxides of the unsymmetrical variety. In this example, Vhe regiochemistry reverses with the reaction conditions. Why ... 

For intramolecular D-A rxns, geometric constraints can now reverse the normal regiochemistry of the addition as compared to the intermolecular rxn. 

When both the 1,3-dipoIe and the dipolarophile are unsymmetrical, there are two possible orientations for addition. Both steric and electronic factors play a role in determining the regioselectivity of the addition. The most generally satisfactory interpretation of the regiochemistry of dipolar cycloadditions is based on frontier orbital concepts. As with the Diels-Alder reaction, the most favorable orientation is that which involves complementary interaction between the frontier orbitals of the 1,3-dipole and the dipolarophile. Although most dipolar cycloadditions are of the type in which the LUMO of the dipolarophile interacts with the HOMO of the 1,3-dipole, there are a significant number of systems in which the relationship is reversed. There are also some in which the two possible HOMO-LUMO interactions are of comparable magnitude. 

Additions of the halogen fluorides to unsaturated steroids [62, 95, 96, 97, 98, 99] and carbohydrates [62, 75] are well known Typical reagent combinations include l,3-dibromo-5,5-dimethylhydantoin (DBH) or the Af-halosuccinimides with hydrogen fluoride Reversal of the expected regiochemistry can be observed with certain steroidal olefins [JOO, 101] (equation 7)... 

Normally, phenylhydrazine reacts with the enol form of 1,1,1-trifluorometh-ylpentane-2,4-dione to give 5-methyl-l-phenyl-3-tnfluoromethylpyrazole as the major product. However, the use of pyrrolidine as a transient carbonyl-blocking group can completely reverse the regiochemistry of the addition and leads to 3-methyl-l-phenyl-5-trifluoromethylpyrazole [102] (equation 88)... 

The use of diphenyl hydrazone 33 has been used in the synthesis of pyrazoles under modified conditions where the hydrazine is released in situ. Some reversal of regiochemistry is seen in the reaction with unsymmetrical dicarbonyls. With aryl hydrazine and diphenyl hydrazone, the ratio of 41 to 42 is 22 1 and 5 1, respectively. 

Reacting 6 with triethyl phosphite (TEP) as the solvent gave compound 60 (01T(57)5453). The bromo derivative 46, with an equimolecular amount of TEP, afforded 29, which could be trasformed into 61 by reacting with an excess of TEP, showing a reversal of the usual regiochemistry observed in the nucleophilic addition of other 3-aminosubsdtuted isothiazole 5,5-dioxides. Reactivity of this new class of isothiazole dioxides was studied (Section II.B.l.a). 

Furthermore, 1,2-addition is sometimes reversible, and in several cases leads to a 1,2 to 1,4 conversion at higher temperatures or when longer reaction times are used6"14. Finally the regiochemistry can be very sensitive to the reaction conditions. 

Thilgen C., Cardullo F., Haldimann R., Isaacs L., Seiler P., Diederich F., Boudon C., Gisselbrecht J. P., Gross M. Synthesis of Multiple Adducts of C60 With Specific Addition Patterns by Simple and Reversible (Templated) Tether-Directed Remote Functionalization Proc. - Electrochem. Soc. 1996 96-10 1260-1271 Keywords fullerene C60, regiochemistry... 

Note that hydrozirconation of 2-vinylfuran gives only the internal product [86] (Scheme 8-16) which probably is the result of the combination of the effects described in this section (i) O-coordination, (ii) aromatic stabihzation, (iii) reduced steric effect of the flat furan ring, which favors the reverse expected regiochemistry in the hydrozirconation reaction of alkenes with [Cp2Zr(H)Cl] (1). 

The regiochemistry of the Heck reaction is determined by the competitive removal of the (3-proton in the elimination step. Mixtures are usually obtained if more than one type of (3-hydrogen is present. Often there is also double-bond migration that occurs by reversible Pd-H elimination-addition sequences. For example, the reaction of cyclopentene with bromobenzene leads to all three possible double-bond isomers.146... 

Two essentially different mechanisms, (i) oxidative cyclization of two 7T-components (formation of metallacycle) and (ii) oxidative addition of reducing or alkylating agents followed by insertion of 7t-components, can operate in these three-component reactions.426 However, the aforementioned phenomena such as the reversal of regiochemistry and the crossover from reductive to alkylative manifolds remain unsolved. 

The regiochemistry of nucleophilic addition to alkene radical cations is a function of the nucleophile and of the reaction conditions. Thus, water adds to the methoxyethene radical cation predominantly at the unsubstituted carbon (Scheme 3) to give the ff-hydroxy-a-methoxyethyl radical. This kinetic adduct is rearranged to the thermodynamic regioisomer under conditions of reversible addition [33]. The addition of alcohols, like that of water, is complicated by the reversible nature of the addition, unless the product dis-tonic radical cation is rapidly deprotonated. This feature of the addition of protic nucleophiles has been studied and discussed by Arnold [5] and Newcomb [84,86] and their coworkers. 

Introduction of a trimethylsilyl group at the terminal alkynyl position of the foregoing chiral mesylates reverses the regiochemistry of the addition reactions (Table 9.35) [50]. In these systems, the allenyl adducts are strongly favored in additions that are highly diastereo- and enantioselective. 

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... 

Tropone itself gives with diazomethane a 3 1 mixture of 1- and 2-methylcycloheptapyrazol-4-ones (143a,b), along with cyclooctatrienone and 2,3-homotropone (72TL1925). Here the regiochemistry of cycloaddition is the reverse of that of diazomethane with simple a,/3-unsaturated carbonyl compounds (80MI1, p.282). The different behavior of tropone and, e.g.. 

If you don t know your reactions, you can t possibly solve a multistep synthesis problem. Knowing the reactions includes the reactants, products, conditions, regiochemistry, and stereochemistry. Flashcards are a useful means of learning the reactions. On the front side of the card, write the reactants and conditions, and on the reverse side, write the products, regiochemistry, and stereochemistry. Learn the cards in one direction first (identifying what s on the back based on what you see on the front), and then learn them in reverse (knowing what s on the front when you look at the back). You must know the reactions backwards and forwards. (Shuffle the deck often.)... 

After finishing a multistep synthesis problem, spend some time working on another problem or task. Then come back and check each step in both the forward and the reverse direction. You should pay particular attention to both the regiochemistry and the stereochemistry of each step. In addition, if one of the steps involves a molecule with more than one functional group, make sure the reaction only alters the desired functional group. 

Due to the increased reactivity of the reaction in the presence of a Lewis acid, the reaction scope was extended to singly activated alkenes. Previous results had shown either no reaction or extremely poor yields. However, under the Lewis acid catalyzed conditions, acrylonitrile furnished a 1 1, endo/exo mixture of products. The addition of the catalyst gave unexpected regiochemistry in the reaction, which is analogous with results described in Grigg s metal catalyzed reactions. These observations in the reversal of regio- and stereocontrol of the reactions were rationalized by a reversal of the dominant, interacting frontier orbitals to a LUMO dipole-HOMO dipolarophile combination due to the ylide-catalyst complex. This complex resulted in a further withdrawal of electrons from the azomethine ylide. 

The intriguing reversal of regiochemistry observed previously in the Ti(0/-Pr)3Cl mediated protocol was also observed in the asymmetric example. Subjection of 355 to cycloaddition with 356 mediated by Ti(Oi-Pr)3Cl/Et3N led to the transesterified product 357 as a single enantioenriched diastereoisomer in 75% yield (Scheme 3.120). 

There are some minor discrepancies in the experimental literature regarding the regiochemistry of this addition. Some workers report a firm preference for para addition, even in situations where the para position is substimted. ° Other studies of similar, but not identical nitrenium ions, show ortho products as the major adducts.It is likely that many of these differences can be traced to the reversibility of the addition process. For example, the initial adduct formed from water addition to arylnitreniums is an oxonium ion (72 or 73), a species that can also... 

Propagation The bromine radical is electron deficient and electrophilic. The radical adds to the double bond, generating a carbon-centred radical. This radical abstracts hydrogen from HBr, giving the product and another bromine radical. The orientation of this reaction is anfi-Markovnikov. The reversal of regiochemistry through the use of peroxides is called the peroxide effect. 

As expected, allylic alcohols and ethers afford v/c-diol derivatives upon hydroboration. However, in the presence of Wilkinson s catalyst, a reverse regiochemistry for the hydroboration is observed [108]. There is the possibility that boron, rather than hydrogen, is transferred from the metal to the olefin. In other words, the boron acts as a donor. 

The selective arylation of azoles, including imidazole, was achieved by Sames. Under the developed conditions, including the use of magnesium oxide as base, imidazole was arylated in the 4-position selectively, while the addition of a stoichiometric amount of copper(I) iodide led to the reversal of the regiochemistry, resulting in the selective formation of 2-phenylimidazole (6.89.),120... 

---