active natural products.8 So we focused our research on the
synthesis of 4-piperidones via addition of ketones to imines
mediated by the radical cation procedure (Table 3).
Scheme 1
.
Proposed Mechanism for Mannich Addition Induced
by Radical Cation
We varied the ketones reacting with the imine radical
cation intermediate and leading to a series of 4-piperidinones.
Straight chain ketones acted well in this reaction (entries 1-3
and 6-13). The ketones having more steric bulk (entries 4
and 5) could also be tolerated in the addition process, but
only traces of the corresponding 4-piperidones were afforded
even after 18 h under the same reaction condition because
the cyclization became difficult due to steric hindrance. From
the stoichiometric point of view, 2 mol of imines was needed
in the cyclization, and we also tried the reaction using 1 in
one molar excess; however, the yields of both products 3
and 4 greatly decreased (not shown in Table 3).9 Futhermore,
we also chose TDBPA+• as the catalyst, but the yield of
4-piperidone was decreased (entry 2).
Next, we screened the reaction by varying the imines
bearing electron-donating or electron-withdrawing groups on
the aromatic ring Ar2, but no cyclization product was found
(only ꢀ-amino ketones were isolated), which implies NO2
on Ar2 exerts the most important effect on the efficiency of
cyclization. We then investigated the substituent effect on
Ar1, but neither electron-donating nor electron-withdrawing
groups showed an obvious effect on cyclization to 4-piperi-
dones (entries 6-15). The reason might lie in that when NO2
was born to Ar2 the electrophilicity of the corresponding
imine radical cation intermediate 1+• was improved dramati-
cally, which made the second addition easier (see Scheme
1). First, the imine loses an electron to form the correspond-
ing radical cation 1+• due to lower oxidation potential (the
oxidation potential of imines is about 1.8 V vs SCE,5a and
the ketones are above 3.0 V vs S.C.E.). 1+• is then trapped
by the enol tautomer of ketones. After the elimination of a
proton producing a N-centered radical which accepts an
electron from another mole of imine to propagate the chain
(or from Ar3N), ꢀ-aminoketone is produced. When an imine
bearing NO2 on Ar2 is involved in this reaction, the
electronphilicity of the corresponding imine radical cation
1+• is getting stronger so that it can add to the enol tautomer
of ꢀ-aminoketone, followed by electron transfer and in-
tramolecular substitution. After the elimination of an aniline,
4-piperidone is generated. In most cases, the decomposition
products of imines, benzaldehydes, were isolated as byprod-
uct, which implied the generation of the imine radical cation.
product, 1,2,6-triaryl-4-piperidone, was isolated in moderate
yield as a single stereoisomer (Table 3). It is well-known
Table 3. Synthesis of 4-Piperidones Induced by Aminium Salts
entry
1
2
time (h)
3 (%)a
4 (%)a
1b
1f
2b
2b
2c
2d
2e
2b
2c
2b
2c
2b
2c
2b
2c
2b
2c
6
6
40 (3k)
42 (3k)
46 (3l)
39 (4a)
35 (4a)
22 (4b)
trace
2c
1f
3b
1f
6
4b
1f
18
18
3
48 (3m)
52 (3n)
39 (3o)
45 (3p)
56 (3q)
40 (3r)
38 (3s)
52 (3t)
33 (3u)
42 (3v)
34 (3w)
36 (3x)
5b
1f
trace
6b
1g
1g
1h
1h
1i
27 (4c)
18 (4d)
36 (4e)
28 (4f)
48 (4 g)
32 (4 h)
39 (4i)
35 (4j)
38 (4k)
40 (4l)
7b
3
8b
3
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9b
3
10b
11b
12b
13b
14b
15b
3
1i
3
1j
6
1j
6
1k
1k
6
6
a Isolated yield. TBPA+• (5 mol %) was added as an initiator.
b
c TDBPA+• (5 mol %) was added as an initiator.
that 4-piperidones are very important building blocks in
organic synthesis.7 In particular, 2,6-disubstituted-4-piperi-
dones are found in the frameworks of many biologically
734
Org. Lett., Vol. 12, No. 4, 2010