Chapter 19, Problem 19.73P

Interpretation Introduction

(a)

Interpretation:

It is to be shown how to carry out the given synthesis by using any reagents necessary.

Concept introduction:

Alkylation of carbonyl compound can take place at the α-carbon via nucleophilic substitution reaction. In this reaction acidic proton of the carbonyl compound is abstracted by the strong base an enolate anion is formed. The attack of this nucleophile takes place at the electrophilic carbon of the alkyl bromide and bromine atom is displaced through the ${\text{S}}_{\text{N}}\text{2}$ mechanism. The reduction of the carbonyl group of a ketone to a methylene (${\text{CH}}_{\text{2}}$) group and an aldehyde to methyl (${\text{CH}}_{\text{3}}$) group by the treatment of hydrazine followed by heating under basic conditions is called Wolff-Kishner reduction. This method is useful for acid-sensitive compound (aldehyde or ketone). LDA is the strong non-nucleophilic base, due to bulky isopropyl groups. Therefore, it abstracts proton of less sterically hindered α-carbon of the carbonyl compound.

Answer to Problem 19.73P

The given synthesis is carried out as:

Explanation of Solution

The given synthesis:

So the given synthesis is carried out below:

In the first step, the nucleophilic addition of the enolate anion to the ethyl bromide takes place shown below:

Note than LDA is sterically hindered strong base, therefore, abstract less sterically hindered proton selectively.

Finally, the carbonyl group is reduced to a corresponding methylene group (${\text{CH}}_{\text{2}}$) by Wolff-Kishner reduction to form the final required product.

Conclusion

It is shown how to carry out the given synthesis by using any reagents necessary.

Interpretation Introduction

(b)

Interpretation:

It is to be shown how to carry out the given synthesis by using any reagents necessary.

Concept introduction:

Alkylation of carbonyl compound can take place at the α carbon via nucleophilic substitution reaction. In this reaction acidic proton of the carbonyl compound is abstracted by the strong base an enolate anion is formed. The attack of this nucleophile takes place at the electrophilic carbon of the alkyl bromide and bromine atom is displaced through ${\text{S}}_{\text{N}}\text{2}$ mechanism. The reduction of the carbonyl group of a ketone to a methylene (${\text{CH}}_{\text{2}}$) group and an aldehyde to methyl (${\text{CH}}_{\text{3}}$) group by the treatment of hydrazine followed by heating under basic conditions is called a Wolff-Kishner reduction. This method is useful for acid-sensitive compound (aldehyde or ketone).

Answer to Problem 19.73P

The given synthesis is carried out as:

Explanation of Solution

The given synthesis is

So the given synthesis is carried out below:

In the first step, the nucleophilic addition of the enolate anion to the ethyl bromide takes place shown below:

The require nucleophile is generated by the treatment of the strong base $\text{NaOH}\text{.}$

Finally, the carbonyl group is reduced to a corresponding methylene group (${\text{CH}}_{\text{2}}$) by Wolff-Kishner reduction to form the final required product.

Conclusion

It is shown how to carry out the given synthesis by using any reagents necessary.

Interpretation Introduction

(c)

Interpretation:

It is to be shown how to carry out the given synthesis by using any reagents necessary.

Concept introduction:

Lithium dialkylcuprate, ${\left(\text{R}\right)}_{\text{2}}\text{CuLi}$, is called a Gilman reagent which possesses a weak nucleophile ${\text{R}}^{\text{-}}$. Since ${\text{R}}^{\text{-}}$ is weak nucleophile adds to the $\text{β-}$ carbon of the $\text{α,β-}$ unsaturated carbonyl compound selectively (rather than the direct addition) and this addition is called conjugate or $\text{1, 4-addtion}$. Alkylation of carbonyl compound can take place at the α carbon via nucleophilic substitution reaction. In this reaction acidic proton of the carbonyl compound is abstracted by the strong base an enolate anion is formed. The attack of this nucleophile takes place at the electrophilic carbon of the alkyl bromide and bromine atom is displaced through ${\text{S}}_{\text{N}}\text{2}$ mechanism. The reduction of the carbonyl group of a ketone to a methylene (${\text{CH}}_{\text{2}}$) group and an aldehyde to methyl (${\text{CH}}_{\text{3}}$) group by the treatment of hydrazine followed by heating under basic conditions is called a Wolff-Kishner reduction. This method is useful for acid-sensitive compound (aldehyde or ketone).

Answer to Problem 19.73P

The given synthesis is carried out as:

Explanation of Solution

The given synthesis is

It is noticed that one ethyl group is added to the 3-position of the original compound, therefore, the conjugate addition must be needed.

So the given synthesis is carried out below:

The first conjugate addition is carried out by the treatment of lithium diethylcuprate, a Gilman reagent with the given starting material. Since the conjugate addition is irreversible to the carbonyl group and regenerated during the workup step.

The above product then treated with ethyl bromide in the presence of a strong base ${\text{NaNH}}_{\text{2}}$. The alkylation takes place at $\text{α-}$ carbon via nucleophilic substitution reaction.

Finally, the carbonyl group is reduced to a corresponding methyl group (${\text{CH}}_{\text{3}}$) by Wolff-Kishner reduction to form the final required product.

Conclusion

It is shown how to carry out the given synthesis by using any reagents necessary.

Interpretation Introduction

(d)

Interpretation:

It is to be shown how to carry out the given synthesis by using any reagents necessary.

Concept introduction:

LDA is the strong non-nucleophilic base, due to bulky isopropyl groups. Therefore, it abstract proton of less sterically hindered α-carbon of the carbonyl compound. The reduction of the carbonyl group of a ketone to a methylene (${\text{CH}}_{\text{2}}$) group and an aldehyde to methyl (${\text{CH}}_{\text{3}}$) group by the treatment of hydrazine followed by heating under basic conditions is called a Wolff-Kishner reduction. This method is useful for acid-sensitive compound (aldehyde or ketone). The protected alcohol in the form of sillylated ether (e.g. OTBDMS) are deprotected by using F- ion. Commonly for that purpose (${\text{Bu}}_{\text{4}}{\text{N}}^{\text{+}}{\text{F}}^{\text{-}}$) or $\text{HI}$ are used.

Answer to Problem 19.73P

The given synthesis is carried out as:

Explanation of Solution

The given synthesis is

It is noticed that the phenyl group is added to the carbonyl carbon of the given starting material. So Grignard reaction carried out first as below:

Since acidic condition required in workup step of Grignard reaction, the protected carbonyl group deprotected automatically because in acidic condition acetal protection also deprotect and the carbonyl group regenerated (right to the above product).

The alkylation of right carbon of the regenerated carbonyl compound is needed and it is done by using the sterically hindered base, LDA followed by methyl bromide. The bromine atom is replaced by a nucleophile (an enolate anion) via ${\text{S}}_{\text{N}}\text{2}$ mechanism. To carry out this operation alcoholic group must be protected because it will react with LDA.

The substrate is first treated with $\text{TBDMS-Cl}$ to protect the OH group shown below:

Now the required alkylation is carried out as below:

Finally, the carbonyl group is reduced to a corresponding methylene group (${\text{CH}}_{\text{2}}$) by Wolff-Kishner reduction and the deprotection of the OH group is done to form the final required product.

The protected OH in the form of OTBDMS is deprotected by the use of the source of ${\text{F}}^{\text{-}}$ ion, for that purpose (${\text{Bu}}_{\text{4}}{\text{N}}^{\text{+}}{\text{F}}^{\text{-}}$) is used.

Conclusion

It is shown how to carry out the given synthesis by using any reagents necessary.