Biomedical Engineering Reference
In-Depth Information
A special feature of this domino sequence is the in situ generation of both cycload-
dition components at room temperature under metal-free conditions. Subsequent
exploratory studies to extend the scope of this domino process lead to the synthesis
of 22 1,4-benzoxazines using 3,4-azaquinone
30a
ox
and various aliphatic amines,
with yields ranging from 5 to 80% (Table 5.9). A high degree of tolerance for the
amine component was demonstrated in this reaction sequence. Interestingly, the ini-
tial cycloadducts derived from phenethylamine building blocks (Table 5.9, entries
4 and 5) underwent further oxidation to afford the stable imines
35d
and
e
.Itis
also noteworthy that single regioisomers are formed from a mixture of two different
amines (Table 5.9, entries 6 to 8).
An alternative one-pot tandem oxidation/IEDDA sequence was developed for
aminophenols
30
red
(R
H, Me) and cyclohexyl-enamine
34
, using a platinum
anode with a higher anodic decomposition potential (Table 5.10). With this procedure,
eight additional 1,4-benzoxazines
35
were prepared (10 to 65%), further expanding
the generality of the reaction sequence (Table 5.10).
=
5.3 ANIONIC DOMINO REACTIONS
In 2007, Wan et al. reported a multicomponent protocol for the conversion of nitriles
into acyl aminals through a domino reaction sequence comprising nitrile hydrozir-
conation, acylation, and nucleophilic additions [17]. The scope of this methodology
was later elaborated to include a Lewis-acid-promoted intramolecular Friedel-Crafts
annulation of the acylimine
38
to give various bicyclic
-alkoxyamides
39
(Scheme
5.13) [18]. In general, this domino sequence proceeds efficientlywith good diastereos-
electivities, making it ideal for library synthesis. Ultimately, a 35-membered bicyclic-
benzyloxy amide library
39
was constructed and provided a high level of structural
novelty compared to the National Institutes of Health small-molecule repository
(SMR).
This reaction cascade is initiated by the treatment of cyanohydrin
36
with Schwartz
reagent [Cp
2
Zr(H)Cl] to give the metalloimine intermediate
37
[19]. Subsequent
treatment with various acid chlorides provided the acylimine
38
, which cyclized to
39
when exposed to a stoichiometric amount of ZnCl
2
. The use of cyanohydrin-benzyl
ethers gave improved yields of the desired amido-bicycles, presumably due to the
lower acylimine tautomerization rates compared to unsubstituted nitrile substrates
or the increased rate of nitrile hydrozirconation due to the inductive effect of the
benzylether. The latter functionality was used to enhance the structural diversity of
this library.
Cyanohydrin benzyl ethers
36a
to
c
were readily prepared using established
protocols (Scheme 5.14) [20]. The library design included a set of 13 commer-
cially available acid chlorides comprised of aliphatic, aromatic, and heteroaromatic
derivatives. Cyanohydrin ether
36a
afforded a series of tetrahydronaphthyl amides
after the hydrozirconation-acylation-cyclization reaction sequence (Table 5.11, 16
to 73%). The resulting stereoisomers were separated using mass-directed HPLC with
subsequent
1
H NMR analysis indicating the major diastereomers to be the syn
