Chemistry Reference
In-Depth Information
drating equivalent to DCC under nearly neutral conditions [1137, 1245]. Dehydra-
tion reactions of formamides 1513 forming isocyanides 1515 have been described
for four model compounds; yields were 25-78%. For mechanistic aspects, see
Section 4.5.1.
General procedure. Isocyanides 1515 [1137]:
To a solution of the formamide 1513 (1
equiv.) and CDC (1 equiv.) in an appropriate solvent, the amine (2 equiv.) was
added dropwise at room temperature. The reaction mixture was stirred at room
temperature (under reflux in some cases), then poured into water and extracted
with dichloromethane. The organic solution was successively washed with 5%
HCl, saturated aq. NaHCO
3
, and water. It was dried (MgSO
4
) and concentrated to
dryness. The residue was purified by short column chromatography (SiO
2
) to give
the isocyanide 1515.
For another application CDC has been employed in specific dehydrosulfurization
reactions to synthesize modified guanidines as potential chiral superbases [1100].
4.5.3
Carbodiimides
In World War II, penicillins proved their worth as antibiotics, curing infections in
a hitherto unprecedented manner. There was a great need for penicillins, which
could by no means be met by isolation from cultures of the fungus penicillium
notatum. It was a challenge for organic chemists to synthesize penicillins, but due
to the extreme sensitivity of the molecules under nearly all conditions (even in
distilled water at pH 7!) they proved very elusive. The key step was forming the b-
lactam moiety, for which all known common coupling methods failed (attempts
to prepare penicillin G provided isolated product yields of just 0.008%). In 1959,
Sheehan succeeded in achieving the total synthesis of penicillin V 1687; the key
step of b-lactam formation was performed with dicyclohexylcarbodiimide (DCC)in
a yield of 5% [1246]. Three years later, the same group were able to increase the
yield of the key intermediate 1686 to 67% in an improved synthesis using 1684 and
diisopropylcarbodiimide 1685 for the key step, but applied another synthetic strat-
egy to obtain penicillin V 1687 [1247].
Because of the convincing results even in penicillin chemistry, due to the
smooth reaction conditions, carbodiimides and particularly DCC became common
coupling reagents in natural compound and peptide chemistry. In combination
with binucleophiles, such as N-hydroxysuccinimide or N-hydroxybenzotriazole, the
method is racemization-free [1248]. Other frequent applications are in esterifica-
tions and general dehydration reactions, and, more recently, in carbodiimide-
mediated multicomponent reactions [1251] (see Section 4.5.3.5). All these reactions
proceed through activated intermediates 1689. Thus, compounds with a carboxylic
function 1688 can be coupled with a nucleophilic compound 1690 to afford the
coupled product 1691 under extremely mild conditions. The resulting by-product
dicyclohexylurea 1693, however, is di
cult to separate because of its ambivalent
solubility properties, which usually complicate the whole work-up procedure.
