Page 178 - Advanced Organic Chemistry Part B - Reactions & Synthesis

150 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
CHAPTER 2 this purpose. The sodium alkoxide is also the active catalyst in procedures that use
Reactions of Carbon sodium metal, such as in Entry 3 in Scheme 2.14. The alkoxide is formed by reaction
Nucleophiles with
Carbonyl Compounds of the alcohol that is formed as the reaction proceeds.
The intramolecular version of ester condensation is called the Dieckmann condens-
ation. 217 It 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 diester 25. 218 Only
27 is formed, because 26 cannot be converted to a stable enolate. If 26, synthesized
by another method, is subjected to the conditions of the cyclization, it is isomerized
to 27 by the reversible condensation mechanism.

O –
O CH3
CO C H NaOEt CH3 CO 2 C 2 H 5
2 2 5
H O CCH (CH ) CHCO C H
C 2 5 2 2 2 3 2 2 5
xylene
CH 3
25
26 NaOEt 27
xylene
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 MgCl , with an amine can also promote Dieckmann
2
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
TiCl in a scale-up synthesis and can be done on a 60-kg scale. The 14-membered
4
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).