148
CHAPTER 2 Reactions of Carbon Nucleophiles with Carbonyl Compounds
149
SECTION 2.3 Acylation of Carbon Nucleophiles
transformation results in theacylationof the carbon nucleophile. This transformation corresponds to the general reaction PathB, as specified at the beginning of this chapter (p. 64).
+ RC X
O
RC CR′2
X EWG O–
RCCR′2
O
EWG R′2C EWG
–
The reaction pattern can be used for the synthesis of 1,3-dicarbonyl compounds and other systems in which an acyl group isto an anion-stabilizing group.
O
R1 X R1 EWG
R2 O + R2CH2EWG
2.3.1. Claisen and Dieckmann Condensation Reactions
An important group of acylation reactions involves esters, in which case the leaving group is alkoxy or aryloxy. The self-condensation of esters is known as the Claisen condensation.216 Ethyl acetoacetate, for example, is prepared by Claisen condensation of ethyl acetate. All of the steps in the mechanism are reversible, and a full equivalent of base is needed to bring the reaction to completion. Ethyl acetoacetate is more acidic than any of the other species present and is converted to its conjugate base in the final step. The-ketoester product is obtained after neutralization.
+ CH3CH2O– CH3CCHCO2CH2CH3 + CH3CH2OH O
CH3CCH2CO2CH2CH3 – O
CH3CH2O– +
CH3CCH2CO2CH2CH3 O
CH2CO2CH2CH3 CH3C OCH2CH3
O–
CH3CO2CH2CH3 + CH3CH2O– –CH2CO2CH2CH3 + CH3CH2OH
+ –CH2CO2CH2CH3 CH3COCH2CH3 O–
CH2CO2CH2CH3 CH3COCH2CH3
O
As a practical matter, the alkoxide used as the base must be the same as the alcohol portion of the ester to prevent product mixtures resulting from ester interchange.
Sodium hydride with a small amount of alcohol is frequently used as the base for ester condensation. The reactive base is the sodium alkoxide formed by reaction of sodium hydride with the alcohol released in the condensation.
+ NaH +
R′OH R′ONa H2
As the final proton transfer cannot occur when -substituted esters are used, such compounds do not condense under the normal reaction conditions, but this limitation
216 C. R. Hauser and B. E. Hudson, Jr.,Org. React.,1, 266 (1942).
150
CHAPTER 2 Reactions of Carbon Nucleophiles with Carbonyl Compounds
can be overcome by use of a very strong base that converts the reactant ester completely to its enolate. Entry 2 of Scheme 2.14 illustrates the use of triphenylmethylsodium for this purpose. The sodium alkoxide is also the active catalyst in procedures that use sodium metal, such as in Entry 3 in Scheme 2.14. The alkoxide is formed by reaction of the alcohol that is formed as the reaction proceeds.
The intramolecular version of ester condensation is called theDieckmann condens- ation.217It is an important method for the formation of five- and six-membered rings and has occasionally been used for formation of larger rings. As ester condensation is reversible, product structure is governed by thermodynamic control, and in situations where more than one product can be formed, the product is derived from the most stable enolate. An example of this effect is the cyclization of the diester25.218Only 27is formed, because26 cannot be converted to a stable enolate. If26, synthesized by another method, is subjected to the conditions of the cyclization, it is isomerized to27by the reversible condensation mechanism.
O CH3 CO2C2H5
O–
CO2C2H5 CH3
NaOEt xylene
26 NaOEt 27
xylene
C2H5O2CCH2(CH2)3CHCO2C2H5 CH3
25
Entries 3 to 8 in Scheme 2.14 are examples of Dieckmann condensations. Entry 6 is a Dieckmann reaction carried out under conventional conditions, followed by decarboxylation. The product is a starting material for the synthesis of a number of sarpagine-type indole alkaloids and can be carried out on a 100-g scale. The combi- nation of a Lewis acid, such as MgCl2, with an amine can also promote Dieckmann cyclization.219 Entry 7, which shows an application of these conditions, is a step in the synthesis of a potential drug. These conditions were chosen to avoid the use of TiCl4 in a scale-up synthesis and can be done on a 60-kg scale. The 14-membered ring formation in Entry 8 was carried out under high dilution by slowly adding the reactant to the solution of the NaHMDS base. The product is a mixture of both possible regioisomers (both the 5- and 7-carbomethoxy derivatives are formed) but a single product is obtained after decarboxylation.
Mixed condensations of esters are subject to the same general restrictions as outlined for mixed aldol reactions (Section 2.1.2). One reactant must act preferentially as the acceptor and another as the nucleophile for good yields to be obtained. Combin- ations that work best involve one ester that cannot form an enolate but is relatively reactive as an electrophile. Esters of aromatic acids, formic acid, and oxalic acid are especially useful. Some examples of mixed ester condensations are shown in Section C of Scheme 2.14. Entries 9 and 10 show diethyl oxalate as the acceptor, and aromatic esters function as acceptors in Entries 11 and 12.
2.3.2. Acylation of Enolates and Other Carbon Nucleophiles
Acylation of carbon nucleophiles can also be carried out with more reactive acylating agents such as acid anhydrides and acyl chlorides. These reactions must
217 J. P. Schaefer and J. J. Bloomfield,Org. React.,15, 1 (1967).
218 N. S. Vul’fson and V. I. Zaretskii,J. Gen. Chem. USSR,29, 2704 (1959).
219 S. Tamai, H. Ushitogochi, S. Sano, and Y. Nagao,Chem. Lett., 295 (1995).
151
SECTION 2.3 Acylation of Carbon Nucleophiles