Synthesis of Highly Substituted Anilines
TABLE 1. Optimization of Direct Organocatalytic Cascade
SCHEME 2. Organocatalytic Cascade Approach to the
Synthesis of Highly Substituted Anilines
Synthesis of o-Hydroxydiarylaminesa
products yieldb
(%)
(h) 4aa 5aa 6aa
Hagemann’s
ester 1a
(equiv)
catalyst
(20 mol %)
solvent
(0.3 M)
time
entry
1
2
3
4
5
6
7
8
proline
DMSO
DMF
1.0
1.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.0
2.0
2.0
2.0
2.0
6
6
1
36
1
1
1
1
1
1
46
32
90
30
87
88
83
88
85
70
40
35
35
proline
diaminec
glycine
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
CH3CN
EtOH
the amination of a variety of Hagemann’s esters 1 with different
nitrosoarenes 2 as shown in Scheme 2. For developing this novel
cascade EA/IA reaction, we need a library of Hagemann’s esters
1, and we synthesized these esters 1 in good yields with minor
modifications of known methods of direct piperidine- or KOt-
Bu-catalyzed cascade K/M/A/DC reactions (Scheme 2 and Table
S1, see the Supporting Information).5
We initiated our studies of the cascade EA/IA reaction by
screening a number of known and novel organocatalysts for
the amination of Hagemann’s ester 1a using 0.5-1.0 equiv of
nitrosobenzene 2a as shown in Table 1.6 Proline-catalyzed the
formation of o-hydroxydiarylamine 4aa in moderate yields in
DMSO and DMF solvents (Table 1, entries 1 and 2) (in all
piperidine
morpholine
benzylamine
pyrrolidine
4
2
2
10
10
4
2
2
10
10
9d pyrrolidine
10
pyrrolidine
pyrrolidine
pyrrolidine
11
12
13
14
10
10
72
72
4aa (5 mol %) DMSO
DMSO
a Reactions were carried out in solvent (0.3 M) with 1.0-2.0 equiv of
1a relative to the 2a in the presence of 20 mol % of catalyst. b Yield refers
to the column purified product. c (S)-1-(2-Pyrrolidinylmethyl)pyrrolidine.
d 5 mol % of pyrrolidine used.
compounds denoted 4xy, 5xy, and 6xy, x is incorporated from
reactant enones 1 and y is incorporated from the reactant
nitrosoarenes 2). Interestingly, catalyst diamine generated the
cascade product 4aa in very good yield in DMSO (Table 1,
entry 3). Secondary amines like piperidine and morpholine
catalysts also furnished the cascade product 4aa in very good
yields with excellent regioselectivity in DMSO solvent (entries
5 and 6). The primary amine, benzylamine, also catalyzed the
formation of cascade product 4aa in good yield (entry 7). The
simple amine, pyrrolidine, catalyzed the cascade EA/IA reaction
to produce 4aa in 88% yield, which was accompanied by 1:1
regioisomers of o-pyrrolidin-1-yldiarylamines 5aa and 6aa in
8% yield (entry 8). Amine-catalyzed cascade EA/IA reactions
are solvent dependent and also autocatalyzed reactions as shown
in Table 1, entries 10-14. The use of 5 mol % of 4aa catalyzed
the cascade EA/IA reaction of 1a and 2a to produce product
4aa in 35% yield. This is a good demonstration of the
involvement of autocatalysis in the present reactions (Table 1,
entry 13). We envisioned the optimized condition to be 25 °C
in DMSO under 5 mol % of pyrrolidine catalysis to furnish
o-hydroxydiarylamine 4aa in 85% yield (entry 9).
In the investigation of EA/IA cascade reactions under
pyrrolidine catalysis, product 4aa was accompanied by interest-
ing diamination products 5aa and 6aa with good conversion in
EtOH via self-catalysis (Table 1, entry 12). To further exploit
formation of this novel structure, we initiated our studies of
the cascade EA/IA reaction by screening a number of known
amines for the diamination of Hagemann’s ester 1a by 0.5 to
1.0 equiv of both nitrosobenzene 2a and amines 3 as shown in
Table 2.
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The use of proline, diamine, and glycine as reagents in
cascade reactions did not furnish the expected diamination
products 5/6 in EtOH via self-catalysis and produced only
amination product 4aa (not shown in Table 2). Interestingly,
pyrrolidine as reagent in self-catalyzed cascade reactions in
J. Org. Chem, Vol. 72, No. 4, 2007 1459