Multicomponent reactions - Zhu.pdf - Index of

hexenamides into primary amides [8] and acids [9] has been reported. The use
of 1-cyclohexenyl isocyanide was, however, limited by its low stability, which prevented
large-scale preparations and shelf-storage. Furthermore, the preparation
of its stable precursors such as 1-formylamino-1-cyclohexanecarbonitrile and 1formylamino-1-cyclohexene
required tedious multi-step procedures [6b]. A convenient
preparation of 1-formylamino-1-cyclohexene, starting from inexpensive cyclohexanone
and formamide, has been reported by Martens and co-workers [8a]. The
same group reported the synthesis of its more stable derivatives 9 and 10 (Scheme
2.4) [8a].
NC NC
9 10
Scheme 2.4. Derivatives of 1-cyclohexen-1-yl isocyanide.
The Ugi group has designed a new class of convertible isocyanides, namely alkyl
2-isocyano-2-methylpropyl carbonates [7], prepared from commercially available
4,4-dimethyl-2-oxazoline. The Ugi-4CR of 11 afforded the expected products 12,
which were converted into N-acyl a-amino acid esters 13 and N-acyl a-amino acids
by in situ hydrolysis (Scheme 2.5) [7].
N O a
CN
O
O OR
11
O
O
N
O
N
O
O
_
+ OR
N
O
13
OR + N
O
a) BuLi, THF, -78 °C,1 h, then ClCO2R, -78 °C to rt, 80%.
b) Isobutyraldehyde, methylamine, acetic acid, MeOH, rt, 24 h, 80-90%
Scheme 2.5. The use of alkyl 2-isocyano-2-methylpropyl carbonates.
b
In general, the hydrolysis of amides requires conditions that are not compatible
with the survival of several functional groups [10]. If the amide nitrogen is linked
to an electron-withdrawing moiety, alkaline hydrolysis of the amide group is easier.
Following this observation Martens and co-workers used 4-methoxy-2-nitrophenyl
isocyanide 14 (or 2-methoxy-4-nitrophenyl isocyanide) as a convertible isocyanide
for the preparation of Peptide Nucleic Acid (PNA) monomers [8a] (for another example,
see Ref. [11]). The Ugi-4CR between isocyanide 14, carboxymethyl nucleo-
O
N
O
12
N H
O
O
2.1 Convertible Isocyanides 35
OR
t-BuOK
O