Biomedical Engineering Reference
In-Depth Information
TABLE 5.7 Representative Pyrimidine-Fused Tetracycles 27
Entry
R
1
R
2
R
3
Time (h)
Yield (%)
a
1
Me
Ph
H
11
27a
,94
27b
,92
b
2
Me
3-NO
2
-Ph
H
4
3
Me
4-NO
2
-Ph
H
7
27c
,87
4
Me
4-CO
2
H-Ph
H
6
27d
,86
5
Me
2,4-F
2
-Ph
H
23
27e
,83
27f
,88(3:1)
c
6
Me
3-Me-Ph
H
10
7
Me
2,4-Me
2
-Ph
H
27
27g
,78
8
Me
4-OH-Ph
H
20
27h
,98
27i
,85
d
9
Me
1,3-Bn-dioxol-5-yl
H
27
10
Me
1-Naph
H
15
27j
,83
11
Bn
Ph
H
3
27k
,98
12
CH
2
CO
2
Et
Ph
H
7
27l
,95
33
e
13
Me
Ph
Me
27m
,78
14
Me
Ph
Et
85
e
27n
,49
a
Isolated yields.
b
Obtained as a single regioisomer (cyclized at C2 of aniline).
c
Obtained as a mixure of regioisomers.
d
Obtained as a single regioisomer [cyclized at C6 of 3,4-(methylenedioxy)aniline].
e
Anilines (1.05 equiv), TsOH (0.05 equiv), in toluene at reflux with a Dean-Stark trap.
to expand the generality of this methodology further (i.e., by
O
-allylation or
N
-propargylation) were unproductive, possibly due to the insufficient reactivity of
the dienophile. Nonetheless, the ease of formation and further functionalization of
tetracycles
27
renders this methodology well suited for the synthesis of an expanded
library of diverse drug discovery candidates. For example, a small sublibrary was
readily assembled through nucleophilic aromatic displacement of the sulfoxide
28
(Scheme 5.11 and Table 5.8).
While investigating the oxidation of primary amines
31/32
to imines
33
using
electrogenerated 3,4-azaquinone catalysts
30
ox
(derived from
o
-aminophenols
30
red
)
,
Largeron, Blattes, Xu, and co-workers observed that this catalytic cycle ceased after
several turnovers [16]. It was determined that the 3,4-azaquinones
30
ox
underwent a
regioselective inverse electron-demand Diels-Alder cycloaddition with the simulta-
neously electrogenerated tautomeric ene-amines
34
to produce the densely function-
alized 1,4-benzoxazines
35
(Scheme 5.12).
