Page 275 - Advanced Organic Chemistry Part B - Reactions & Synthesis

Two factors are responsible for the reactivity of the imidazolides as acylating reagents. 247
One is the relative weakness of the “amide” bond. Owing to the aromatic character
of imidazole nitrogens, there is little of the N → C=O delocalization that stabilizes SECTION 3.4
normal amides. The reactivity of the imidazolides is also enhanced by protonation of Interconversion of
Carboxylic Acid
the other imidazole nitrogen, which makes the imidazole ring a better leaving group. Derivatives

O O
H +
Nu: +RC N N Nu CR + N NH

Imidazolides can also be activated by N-alkylation with methyl triflate. 116 Imidazolides
react with alcohols on heating to give esters and react at room temperature with amines
to give amides. Imidazolides are particularly appropriate for acylation of acid-sensitive
materials.
Dicyclohexylcarbodiimide (DCCI) is an example of a reagent that converts
carboxylic acids to reactive acylating agents. This compound has been widely applied
in the acylation step in the synthesis of polypeptides from amino acids 117 (see also
Section 13.3.1). The reactive species is an O-acyl isourea. The acyl group is highly
reactive because the nitrogen is susceptible to protonation and the cleavage of the
acyl-oxygen bond converts the carbon-nitrogen double bond of the isourea to a more
stable carbonyl group. 118

O NR
RCO H+RN C NR RC O CNHR
2
O NR O O
H +
Nu: + RC O CNHR RCNu + RNHCNHR

The combination of carboxyl activation by DCCI and catalysis by DMAP provides a
useful method for in situ activation of carboxylic acids for reaction with alcohols. The
reaction proceeds at room temperature. 119

DCCI
Ph CHCO H + C H OH Ph CHCO C H
2 2 5
2
2
2
2 5
DMAP
2-Chloropyridinium 120 and 3-chloroisoxazolium 121 cations also activate carboxy
groups toward nucleophilic attack. In each instance the halide is displaced from the
heterocycle by the carboxylate via an addition-elimination mechanism. Nucleophilic
attack on the activated carbonyl group results in elimination of the heterocyclic ring,
with the departing oxygen being converted to an amidelike structure. The positive

116
G. Ulibarri, N. Choret, and D. C. H. Bigg, Synthesis, 1286 (1996).
117 F. Kurzer and K. Douraghi-Zadeh, Chem. Rev., 67, 107 (1967).
118 D. F. DeTar and R. Silverstein, J. Am. Chem. Soc., 88, 1013, 1020 (1966); D. F. DeTar, R. Silverstein,
and F. F. Rogers, Jr., J. Am. Chem. Soc., 88, 1024 (1966).
119
A. Hassner and V. Alexanian, Tetrahedron Lett., 4475 (1978); B. Neises and W. Steglich, Angew.
Chem. Int. Ed. Engl., 17, 522 (1978).
120 T. Mukaiyama, M. Usui, E. Shimada, and K. Saigo, Chem. Lett., 1045 (1975).
121
K. Tomita, S. Sugai, T. Kobayashi, and T. Murakami, Chem. Pharm. Bull., 27, 2398 (1979).