Vicinal difunctionalization
Encyclopedia
Vicinal difunctionalization refers to a chemical reaction
involving transformations at two adjacent centers (most commonly carbons). This transformation can be accomplished in α,β-unsaturated carbonyl compounds via the conjugate addition of a nucleophile
to the β-position followed by trapping of the resulting enolate with an electrophile
at the α-position. When the nucleophile is an enolate and the electrophile a proton
, the reaction is called Michael addition.
. Activated double bonds represent a useful handle for vicinal difunctionalization because they can act as both nucleophile
s and electrophile
s—one carbon is necessarily electron poor, and the other electron rich. In the presence of a nucleophile and an electrophile, then, the two carbons of a double bond can act as a "relay," mediating electron flow from the nucleophile to the electrophile with the formation of two, rather than the usual one, chemical bonds.
(1)
Most often, the nucleophile
employed in this context is an organometallic compound and the electrophile is an alkyl halide.
When the nucleophile is an organometallic reagent, the mechanisms of the first step can vary. Whether reactions take place by ionic or radical mechanisms is unclear in some cases. Research has shown that the second step may even proceed via single-electron transfers when the reduction potential of the electrophile is low. A general scheme involving ionic intermediates is shown below.
(2)
Lithium organocuprates undergo oxidative addition to enones to give, after reductive elimination of an organocopper(III) species, β-substituted lithium enolates.
In any case, the second step is well described in all cases as the reaction of an enolate with an electrophile. The two steps may be carried out as distinct experimental operations if the initially formed enolate is protected after β-addition. If the two steps are not distinct, however, the counterion of the enolate is determined by the counterion of the nucleophilic starting material and can influence the reactivity of the enolate profoundly.
is common in conjugate addition reactions. Thus, in cyclic substrates, a trans relationship between substituents on the α- and β-carbons is common. The configuration at the α-position is less predictable, especially in cases when epimerization can occur. On the basis of steric approach control, the new α-substituent is predicted to be trans to the new β-substituent, and this is observed in a number of cases.
(3)
(4)
(5)
When unsymmetrical cuprates are employed, the group whose carbon-copper bond contains less s character is almost always transferred to the β-position. A few exceptions exist, however. In the example below, conducting the reaction in THF led to transfer of the vinyl moiety, while other solvents promoted methyl transfer.
(6)
Enolates can also be used as nucleophiles for vicinal difunctionalization reactions. To prevent simple Michael addition (which culminates in protonation of the enolate intermediate), trapping by the electrophile must be intramolecular.
(7)
Considerations of the electrophile should take into account the nature of the conjugate enolate generated after the first step. Relatively reactive alkylating agents should be used, especially in cases involving the addition of cuprates (enolates resulting from the addition of cuprates are often unreactive). Oxophilic electrophiles should be avoided, if C-alkylation is desired. Electrophiles should also lack hydrogens acidic enough to be deprotonated by an enolate.
(8)
Because the addition step is highly sensitive to steric effects, β-substituents are likely to slow the reaction. Acetylenic and allenic substrates react to give products with some retained unsaturation.
(9)
(10)
Because the reaction creates two new bonds with a moderately high degree of stereocontrol, it represents a highly convergent synthetic method.
methods are necessary to verify the purity of reagents. A number of efficient titration methodologies exist.
Usually, vicinal difunctionalizations are carried out in one pot, without the intermediacy of a neutral protected enolate. However, in specific cases it may be necessary to protect the intermediate of β-addition. Before reaching this point, however, solvent and nucleophile screens, order of addition adjustments, and counterion adjustments can be made to optimize the one-pot process for a particular combination of carbonyl compound, nucleophile, and alkylating (or acylating) agent. Solvent adjustments between the two steps are common; if one solvent is used, tetrahydrofuran
is the solvent of choice. Polar aprotic solvents should be avoided for the conjugate addition step. Concerning temperature, conjugate additions are usually carried out at low temperatures (-78 °C), while alkylations are carried out at slightly higher temperatures (0 to -30 °C). Less reactive alkylating agents may require room temperature.
To 6.25 g (50 mmol) of 4,4-dimethyl-2-cyclohexen-1-one and 0.5 g (5.6 mmol) of cuprous cyanide in 400 mL of diethyl ether at –23° under argon
was added 100 mL (~0.75 M in diethyl ether) of 5-trimethylsilyl-4-pentynylmagnesium iodide during 4 hours. Methyl chloroformate
(8 mL, 100 mmol) was added and stirring continued for 1 hour at –23° and 0.5 hour at room temperature. Hydrochloric acid
(100 mL, 2.0 M) then was added and the organic phase separated and dried with magnesium sulfate. The solvent was removed and the residue chromatographed on silica gel using 5% diethyl ether
–petroleum ether
to give methyl 3,3-dimethyl-6-oxo-2-[5-(trimethylsilyl)-4-pentynyl]cyclohexanecarboxylate, 9.66 g (60%). IR 2000, 2140, 1755, 1715, 1660, 1615, 1440, 1280, 1250, 1225, 1205, and 845 cm–1; 1H NMR ( CDCl3) δ 0.13 (s, 9H), 0.93 (s, 3H), 1.02 (s, 3H), 1.2–2.3 (m, 11H), 3.74 (s, 3H). Anal. Calc. for C18H30O3Si: C, 67.05; H, 9.4. Found: C, 67.1; H, 9.65.
Chemical reaction
A chemical reaction is a process that leads to the transformation of one set of chemical substances to another. Chemical reactions can be either spontaneous, requiring no input of energy, or non-spontaneous, typically following the input of some type of energy, such as heat, light or electricity...
involving transformations at two adjacent centers (most commonly carbons). This transformation can be accomplished in α,β-unsaturated carbonyl compounds via the conjugate addition of a nucleophile
Nucleophile
A nucleophile is a species that donates an electron-pair to an electrophile to form a chemical bond in a reaction. All molecules or ions with a free pair of electrons can act as nucleophiles. Because nucleophiles donate electrons, they are by definition Lewis bases.Nucleophilic describes the...
to the β-position followed by trapping of the resulting enolate with an electrophile
Electrophile
In general electrophiles are positively charged species that are attracted to an electron rich centre. In chemistry, an electrophile is a reagent attracted to electrons that participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile...
at the α-position. When the nucleophile is an enolate and the electrophile a proton
Proton
The proton is a subatomic particle with the symbol or and a positive electric charge of 1 elementary charge. One or more protons are present in the nucleus of each atom, along with neutrons. The number of protons in each atom is its atomic number....
, the reaction is called Michael addition.
Introduction
Vicinal difunctionalization reactions, most generally, lead to new bonds at two adjacent carbon atoms. Often this takes place in a stereocontrolled fashion, particularly if both bonds are formed simultaneously, as in the Diels-Alder reactionDiels-Alder reaction
The Diels–Alder reaction is an organic chemical reaction between a conjugated diene and a substituted alkene, commonly termed the dienophile, to form a substituted cyclohexene system. The reaction can proceed even if some of the atoms in the newly formed ring are not carbon...
. Activated double bonds represent a useful handle for vicinal difunctionalization because they can act as both nucleophile
Nucleophile
A nucleophile is a species that donates an electron-pair to an electrophile to form a chemical bond in a reaction. All molecules or ions with a free pair of electrons can act as nucleophiles. Because nucleophiles donate electrons, they are by definition Lewis bases.Nucleophilic describes the...
s and electrophile
Electrophile
In general electrophiles are positively charged species that are attracted to an electron rich centre. In chemistry, an electrophile is a reagent attracted to electrons that participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile...
s—one carbon is necessarily electron poor, and the other electron rich. In the presence of a nucleophile and an electrophile, then, the two carbons of a double bond can act as a "relay," mediating electron flow from the nucleophile to the electrophile with the formation of two, rather than the usual one, chemical bonds.
(1)
Most often, the nucleophile
Nucleophile
A nucleophile is a species that donates an electron-pair to an electrophile to form a chemical bond in a reaction. All molecules or ions with a free pair of electrons can act as nucleophiles. Because nucleophiles donate electrons, they are by definition Lewis bases.Nucleophilic describes the...
employed in this context is an organometallic compound and the electrophile is an alkyl halide.
Prevailing Mechanism
The mechanism proceeds in two stages: β-nucleophilic addition to the unsaturated carbonyl compound, followed by electrophilic substitution at the α-carbon of the resulting enolate.When the nucleophile is an organometallic reagent, the mechanisms of the first step can vary. Whether reactions take place by ionic or radical mechanisms is unclear in some cases. Research has shown that the second step may even proceed via single-electron transfers when the reduction potential of the electrophile is low. A general scheme involving ionic intermediates is shown below.
(2)
Lithium organocuprates undergo oxidative addition to enones to give, after reductive elimination of an organocopper(III) species, β-substituted lithium enolates.
In any case, the second step is well described in all cases as the reaction of an enolate with an electrophile. The two steps may be carried out as distinct experimental operations if the initially formed enolate is protected after β-addition. If the two steps are not distinct, however, the counterion of the enolate is determined by the counterion of the nucleophilic starting material and can influence the reactivity of the enolate profoundly.
Stereochemistry
Steric approach controlSteric effects
Steric effects arise from the fact that each atom within a molecule occupies a certain amount of space. If atoms are brought too close together, there is an associated cost in energy due to overlapping electron clouds , and this may affect the molecule's preferred shape and reactivity.-Steric...
is common in conjugate addition reactions. Thus, in cyclic substrates, a trans relationship between substituents on the α- and β-carbons is common. The configuration at the α-position is less predictable, especially in cases when epimerization can occur. On the basis of steric approach control, the new α-substituent is predicted to be trans to the new β-substituent, and this is observed in a number of cases.
(3)
Nucleophiles and Electrophiles
Organocopper reagents are the most common nucleophiles for the β-addition step. These reagents can be generated catalytically in the presence of Grignard reagents using either copper(I) or copper(II) salts.(4)
(5)
When unsymmetrical cuprates are employed, the group whose carbon-copper bond contains less s character is almost always transferred to the β-position. A few exceptions exist, however. In the example below, conducting the reaction in THF led to transfer of the vinyl moiety, while other solvents promoted methyl transfer.
(6)
Enolates can also be used as nucleophiles for vicinal difunctionalization reactions. To prevent simple Michael addition (which culminates in protonation of the enolate intermediate), trapping by the electrophile must be intramolecular.
(7)
Considerations of the electrophile should take into account the nature of the conjugate enolate generated after the first step. Relatively reactive alkylating agents should be used, especially in cases involving the addition of cuprates (enolates resulting from the addition of cuprates are often unreactive). Oxophilic electrophiles should be avoided, if C-alkylation is desired. Electrophiles should also lack hydrogens acidic enough to be deprotonated by an enolate.
α,β-Unsaturated Carbonyl Compounds
Cyclic α,β-unsaturated ketones are the most commonly employed substrates for vicinal difunctionalization. They tend to be more reactive than acyclic analogues and undergo less direct addition than aldehydes. Amides and esters can be used to encourage conjugate addition in cases when direct addition may be competitive (as in the addition of organolithium compounds).(8)
Because the addition step is highly sensitive to steric effects, β-substituents are likely to slow the reaction. Acetylenic and allenic substrates react to give products with some retained unsaturation.
(9)
Synthetic Applications
A large number of examples of vicinal difunctionalization of unsaturated carbonyl compounds exist in the literature. In one example, the difunctionalization of unsaturated lactone 1 was employed en route to isostegane. This transformation was accomplished in one pot.(10)
Because the reaction creates two new bonds with a moderately high degree of stereocontrol, it represents a highly convergent synthetic method.
Typical Conditions
Organometallic nucleophiles used for conjugate additions are most often prepared in situ. The use of anhydrous equipment and inert atmosphere is necessary. Because these factors are sometimes difficult to control and the strength of freshly prepared reagents can vary substantially, titrationTitration
Titration, also known as titrimetry, is a common laboratory method of quantitative chemical analysis that is used to determine the unknown concentration of an identified analyte. Because volume measurements play a key role in titration, it is also known as volumetric analysis. A reagent, called the...
methods are necessary to verify the purity of reagents. A number of efficient titration methodologies exist.
Usually, vicinal difunctionalizations are carried out in one pot, without the intermediacy of a neutral protected enolate. However, in specific cases it may be necessary to protect the intermediate of β-addition. Before reaching this point, however, solvent and nucleophile screens, order of addition adjustments, and counterion adjustments can be made to optimize the one-pot process for a particular combination of carbonyl compound, nucleophile, and alkylating (or acylating) agent. Solvent adjustments between the two steps are common; if one solvent is used, tetrahydrofuran
Tetrahydrofuran
Tetrahydrofuran is a colorless, water-miscible organic liquid with low viscosity at standard temperature and pressure. This heterocyclic compound has the chemical formula 4O. As one of the most polar ethers with a wide liquid range, it is a useful solvent. Its main use, however, is as a precursor...
is the solvent of choice. Polar aprotic solvents should be avoided for the conjugate addition step. Concerning temperature, conjugate additions are usually carried out at low temperatures (-78 °C), while alkylations are carried out at slightly higher temperatures (0 to -30 °C). Less reactive alkylating agents may require room temperature.
Example Procedure
(11)To 6.25 g (50 mmol) of 4,4-dimethyl-2-cyclohexen-1-one and 0.5 g (5.6 mmol) of cuprous cyanide in 400 mL of diethyl ether at –23° under argon
Argon
Argon is a chemical element represented by the symbol Ar. Argon has atomic number 18 and is the third element in group 18 of the periodic table . Argon is the third most common gas in the Earth's atmosphere, at 0.93%, making it more common than carbon dioxide...
was added 100 mL (~0.75 M in diethyl ether) of 5-trimethylsilyl-4-pentynylmagnesium iodide during 4 hours. Methyl chloroformate
Methyl chloroformate
Methyl chloroformate is the methyl ester of chloroformic acid. It is also known as methyl chlorocarbonate, and is an oily liquid with a colour that is anywhere from yellow to colorless. It is also known for its pungent odour...
(8 mL, 100 mmol) was added and stirring continued for 1 hour at –23° and 0.5 hour at room temperature. Hydrochloric acid
Hydrochloric acid
Hydrochloric acid is a solution of hydrogen chloride in water, that is a highly corrosive, strong mineral acid with many industrial uses. It is found naturally in gastric acid....
(100 mL, 2.0 M) then was added and the organic phase separated and dried with magnesium sulfate. The solvent was removed and the residue chromatographed on silica gel using 5% diethyl ether
Diethyl ether
Diethyl ether, also known as ethyl ether, simply ether, or ethoxyethane, is an organic compound in the ether class with the formula . It is a colorless, highly volatile flammable liquid with a characteristic odor...
–petroleum ether
Petroleum ether
Petroleum ether, also known as benzine, VM&P Naphtha, Petroleum Naphtha, Naphtha ASTM, Petroleum Spirits, X4 or Ligroin, is a group of various volatile, highly flammable, liquid hydrocarbon mixtures used chiefly as nonpolar solvents...
to give methyl 3,3-dimethyl-6-oxo-2-[5-(trimethylsilyl)-4-pentynyl]cyclohexanecarboxylate, 9.66 g (60%). IR 2000, 2140, 1755, 1715, 1660, 1615, 1440, 1280, 1250, 1225, 1205, and 845 cm–1; 1H NMR ( CDCl3) δ 0.13 (s, 9H), 0.93 (s, 3H), 1.02 (s, 3H), 1.2–2.3 (m, 11H), 3.74 (s, 3H). Anal. Calc. for C18H30O3Si: C, 67.05; H, 9.4. Found: C, 67.1; H, 9.65.