20.10 Conjugate Additions

Hornback_Ch20_858-917 12/16/04 12:05 PM Page 894

894 CHAPTER 20 ■ ENOLATE AND OTHER CARBON NUCLEOPHILES

20.10 Conjugate Additions

The conjugate addition of nucleophiles to ,-unsaturated carbonyl compounds at the -position was described in Section 18.10. Enolate and related carbanion nucleo- philes also add in a conjugate manner to ,-unsaturated carbonyl compounds in a process known as the Michael reaction or Michael addition. In many of the exam- ples the enolate ion is one that is stabilized by two carbonyl (or similar) groups. The ,-unsaturated compound is called the Michael acceptor.

O O O X O X X C – – – – X C OCH2CH3 CH3CH2O C CH2 CH3 C– – W NaOEt W W – CH CH3 CH2 CH CH2 (92%) X W W CH C–CH H C–C 2 X 3 3 X Michael O O acceptor

The mechanism for the Michael reaction is shown in Figure 20.6. Only a catalytic amount of base is needed because the initial adduct is itself an enolate anion and is ba- sic enough to deprotonate the dicarbonyl compound, allowing additional reaction to oc- cur. Other examples of the Michael reaction are provided in the following equations: O O

CO2Et W NaOEt CH2 CO– 2Et (90%) W CO2Et CH – CO2Et

O O X CPN X C– – W NaOEt C– – P CH OEt CH2 N C CH2 OEt (73%) X W W W – CH2 CO2Et CH CH2 W EtO2C

With stronger bases, less stable enolate anions can be generated and used in the Michael reaction:

N O O Ph NaNH2 Ph (70%) N

2-Propenenitrile 2-Phenylcyclohexanone Hornback_Ch20_858-917 12/16/04 12:05 PM Page 895

20.10 ■ CONJUGATE ADDITIONS 895

Figure 20.6 2 The enolate nucleophile adds to the ␤-carbon MECHANISM OF THE 1 The enolate anion of the ␤-dicarbonyl of an ␣,␤-unsaturated ketone (or ester or MICHAEL REACTION. compound is generated in the usual manner. nitrile), which is called the Michael acceptor.

O O X X CH –C CH –C 3 W 3 W 1 – HC–H HC . W . . W –. – EtOC .O. . CH2CH3 EtOC X X O O Enolate anion O O X 2 X CH –C H C–C–CH– CH 3 W 3 2 HC–H Michael acceptor O W O X X EtOC O H CCH3 X O CCH3

X W W X . . – W – – – – O – – – – H3C C CH CH2 CH H3C C CH CH2 CH W 3 W COEt COEt X X O O

The product, formed in 92% yield in this The product of this addition is an enolate ion. case, has a bond from the ␣-carbon of the 3 This ion reacts as a base with ethyl aceto- ␤ original enolate ion to the -carbon of the acetate to regenerate another enolate ion, so Michael acceptor. only a catalytic amount of base is needed for the reaction.

PRACTICE PROBLEM 20.7

Show the product of this reaction:

O O O X X X NaOEt CH œCHCOEt CH CCH COEt 2 3 2 EtOH

Solution Identify the electrophile and the nucleophile. The base (NaOEt) removes the most acidic hydrogen, the one on the carbon between the carbonyl groups of ethyl acetoac- etate, to generate the enolate anion. This nucleophile then attacks at the -carbon of the Michael acceptor: O O O O O X – X X X X – – – –

CH C C. . H COEt CH CHCOEt CH CCH CH CH COEt 3 2 3 W 2 2

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896 CHAPTER 20 ■ ENOLATE AND OTHER CARBON NUCLEOPHILES

PROBLEM 20.25 Show the products of these reactions: O O O O O X X X NaOEt X X NaOEt a) CH œCHCCH EtOCCH COEt b) PhCHœCHCPh EtOCCH CN 2 3 2 EtOH 2 EtOH O

NaNH œ 2 c) CH2 CHCN

PROBLEM 20.26 Click Coached Tutorial Problems Explain why the Michael reaction of 2-phenylcyclohexanone with 2-propenenitrile for more practice with the gives the product shown in the equation on page 894 rather than this product: Michael Reaction. N O Ph

The Michael reaction in combination with an aldol condensation provides a useful method for the construction of six-membered rings in a process termed the Robinson annulation. In the following example a tertiary amine is used as the base to catalyze the conjugate addition. Then, treatment with sodium hydroxide causes an intramolecu- lar aldol condensation to occur.

O O O O O NaOH

R3N

Michael (70%) Aldol (85%) addition condensation

Often, the Michael addition product is not isolated. Instead, the intramolecular aldol condensation occurs immediately, and the new six-membered ring is formed, as shown in the following equation. (However, when you are attempting to write the product of such a reaction, it is best to first write the product of Michael addition and then write the final product that results from the aldol condensation.) Hornback_Ch20_858-917 12/16/04 12:05 PM Page 897

20.10 ■ CONJUGATE ADDITIONS 897

O CO2Et CO2Et NaOEt (59%) O O

Ethyl 1-Penten-3-one 2-oxocyclohexanecarboxylate

PROBLEM 20.27 Show the intermediate aldol product in the Robinson annulation reaction of ethyl 2-oxocyclohexanecarboxylate with 1-penten-3-one.

PRACTICE PROBLEM 20.8

Show the product of this Robinson annulation:

O O

KOH

O

Solution The base removes the most acidic hydrogen, and the resulting enolate anion undergoes a conjugate addition with the Michael acceptor: O H C O 3 O O

. –. H

O O

This product then undergoes an aldol condensation to give the final product: O . . – O H2C O

O O Hornback_Ch20_858-917 12/16/04 12:05 PM Page 898

898 CHAPTER 20 ■ ENOLATE AND OTHER CARBON NUCLEOPHILES

PROBLEM 20.28 Show the product of this reaction:

O O

CH3 KOH O

20.11 Synthesis

The reactions presented in this chapter are very important in synthesis because they all re- sult in the formation of carbon–carbon bonds. As we have seen, the best way to approach a synthesis problem is to employ retrosynthetic analysis, that is, to work backward from the target molecule to simpler compounds until a readily available starting material is reached. (Elias J. Corey, winner of the 1990 Nobel Prize in chemistry for “his develop- ment of the theory and methodology of organic synthesis,” coined the term retrosynthetic analysis and formalized much of its logic. He also developed numerous new reagents, in- cluding the dithiane anion nucleophile discussed in Section 20.9, and synthesized a large number of natural products, including many prostaglandins [Section 28.9].) Recall that it is helpful in retrosynthetic analysis to recognize that certain structural features in the tar- get suggest certain reactions. For example, we learned in Chapter 18 that an alcohol tar- get compound suggests that a Grignard reaction might be used in its synthesis. Let’s look at the reactions presented in this chapter in terms of their products so that we might more easily recognize the synthetic reactions that are suggested by the pres- ence of certain features in the target compound. Alkylations of ketones, esters, and nitriles add an alkyl group to the -carbon of compounds containing these functional groups. Therefore, a target molecule that is a ketone, ester, or nitrile with an alkyl group(s) attached to its -carbon suggests the use of one of these alkylation reactions, as illustrated in the following equations using ret- rosynthetic arrows:

Target Compound Starting Material

R O ketone O W X alkylation X – – – – – – R' CH C R" R' CH2 C R"

R O ester O W X alkylation X – – – – – – R' CH C OEt R' CH2 C OEt

R nitrile W alkylation – – P – – P R' CH C N R' CH2 C N

The acetoacetic ester synthesis produces a methyl ketone with an alkyl group(s) substituted on the -carbon, whereas the malonic ester synthesis produces a