Page 280 - Advanced Organic Chemistry Part B - Reactions & Synthesis

252 examples of macrocyclizations. Entry 9 uses the di-2-pyridyl disulfide-Ph P method.
3
The cyclization was done in approximately 0 02M acetonitrile by dropwise addition
CHAPTER 3 of the disulfide. Entries 10 and 11 are examples of application of the Yamaguchi
Functional Group macrolactonization procedure via the mixed anhydride with 2,4,6-trichlorobenzoyl
Interconversion
by Substitution, chloride. The reaction in Entry 12 uses BOP-Cl as the coupling reagent. This particular
Including Protection and reagent gave the best results among the several alternatives that were explored. Further
Deprotection
discussion of this reagent can be found in Section 13.3.1. Entry 13 is an example of
the use of the DCCI-DMAP reagent combination.

3.4.2. Fischer Esterification

As noted in the preceding section, one of the most general methods of synthesis of
esters is by reaction of alcohols with an acyl chloride or other activated carboxylic acid
derivative. Section 3.2.5 dealt with two other important methods, namely, reactions
with diazoalkanes and reactions of carboxylate salts with alkyl halides or sulfonate
esters. There is also the acid-catalyzed reaction of carboxylic acids with alcohols,
which is called the Fischer esterification.

RCO H + R′OH H + RCO R′ + H O
2
2
2
This is an equilibrium process and two techniques are used to drive the reaction to
completion. One is to use a large excess of the alcohol, which is feasible for simple
and inexpensive alcohols. The second method is to drive the reaction forward by
irreversible removal of water, and azeotropic distillation is one way to accomplish
this. Entries 1 to 4 in Scheme 3.5 are examples of acid-catalyzed esterifications. Entry
5 is the preparation of a diester starting with an anhydride. The initial opening of the
anhydride ring is followed by an acid-catalyzed esterification.

3.4.3. Preparation of Amides

The most common method for preparation of amides is the reaction of ammonia or
a primary or secondary amine with one of the reactive acylating reagents described in
Section 3.4.1. Acid anhydrides give rapid acylation of most amines and are convenient
if available. However, only one of the two acyl groups is converted to an amide.
When acyl halides are used, some provision for neutralizing the hydrogen halide that
is formed is necessary because it will react with the amine to form the corresponding
salt. The Schotten-Baumann conditions, which involve shaking an amine with excess
anhydride or acyl chloride and an alkaline aqueous solution, provide a very satisfactory
method for preparation of simple amides.

O O
NaOH
NH + PhCCl N CPh
90% Ref. 131
A great deal of work has been done on the in situ activation of carboxylic acids
toward nucleophilic substitution by amines. This type of reaction is fundamental
for synthesis of polypeptides (see also Section 13.3.1). Dicyclohexylcarbodiimide
131
C. S. Marvel and W. A. Lazier, Org. Synth., I, 99 (1941).