A Route to Carbasugar Analogues - Jonathan Clayden - The ...

1.3 – Nucleophilic dearomatisation
1.3.1.c Strained amides
Tertiary amides are often used to direct metalation of aromatic rings and are not prone
to direct addition. During conformational studies of secondary amides, Clayden found
that tetramethylpiperidenes 22 underwent conjugative addition rather than the expected
ortho-lithiation.
R R’ E 23 / %
O N
O N
i) RLi, THF R
ii) E
E
R'
R
22 23
Table 1.2 – dearomatising addition to
TMP amides 17,18
a s-Bu H MeI 55 *
b Me OMe MeI 22
c n-Bu OMe MeI 40
d s-Bu OMe MeI 71 *
e s-Bu OMe EtI 51 *
f s-Bu OMe BnBr 61 *
g s-Bu OMe Me 2 CO 32 *
h s-Bu OMe NH 4 Cl 76 *
* 3:1 exocyclic d.r.
Only trans-adducts were isolated and both nucleophilic and electrophilic additions
were highly regio- and stereoselective, with the mass balance mostly identified as
starting material. The unexpected reactivity is attributed to an amide in which the
ground state is destabilised by torsional strain, reducing the n N →π* C=O interaction and
allowing the carbonyl to accept more electron density from the aromatic system, whilst
direct addition is prevented by the TMP geminal dimethyl groups. Whilst the reduced
π* interaction is not observed in the IR absorption of amides 22 (1620 cm -1 ) this
appears to be the most likely explanation.
22