G. Cozzi et al.
FULL PAPERS
enantiomeric excesses obtained were quite low, and proba-
bly some p interactions among the carbocation and the alde-
hyde were taking place, although we do not have a detailed
explanation for this behavior. We also investigated the
effect of the counter-anion in the reaction by exchanging the
iodide with ꢁSbF6 (hexafluoroantimonate) through silver
metathesis. The reaction conduced at room temperature was
faster than at 48C (Table 3, entry 4 vs 1), but a lower enan-
tiomeric excess was recorded.
To examine the behavior of the stereogenic carbocation,
flavylium triflate (4) was readily synthesized by the de-
scribed procedure.[19] In general, flavylium ions are basic
constituents of the anthocyanin pigment in plants. Besides
their use as food colorants and dyes, an increased attention
over their synthesis was also determined by their biological
properties.[20] Electrophilicity properties of the flavylium
cation were described by Mayr.[19] The flavylium ion consid-
ered in our study is positioned at ꢁ3.45 of the Mayr scale.
From the application of Equation (2), it is possible to con-
clude that flavylium will react with nucleophiles of N>ꢁ1.5.
As enamines are strong nucleophiles, positive reactivity is
expected. In fact, we observed (Table 4) the formation of
the desired products in the reaction of the aldehydes 7a–c
in the presence of the MacMillan imidazolidinonium catalyst
5 used in a catalytic amount (20 mol%). It is worth men-
moderate to good with linear aldehydes, whereas the yields
were reduced when operating with hindered aldehydes.
The results in terms of stereoselectivity of the process can
be rationalized in relation to the different reactivity of the
carbocations. With the less electrophilic carbocations 2 and
3, moderate to low selectivity was obtained at room temper-
ature. The reaction became more selective at low tempera-
tures with the more electrophilic carbocations 1 and 4. The
inversion of absolute configuration of the products isolated
with linear aldehydes in the case of the carbocation 1 is par-
ticularly intriguing. The results are kinetically controlled. In
fact the isolated product 8a of S configuration, obtained in
the reaction at ꢁ258C, is not equilibrated to the R enantio-
mer in the presence of the MacMillan imidazolidinonium
catalyst 6 at room temperature, and the enantiomeric excess
does not change over 6–8 h. It is commonly assumed that
the MacMillan imidazolidinone catalyst forms selectively E
enamine isomer I with aldehydes, which avoids sterical inter-
action with the tert-butyl group (Scheme 2.[21] The small
facial preference showed by carbocation 1, a function of the
temperature, could be related to the smaller size of the car-
bocation, relative to the others.
The attack on the Si face is favored at low temperature
with linear aldehydes. With a more hindered aldehyde
(Table 1, entry 9–11), the carbocation cannot approach from
both sides of the nucleophile, at
low temperatures and at room
temperature. The peculiar be-
Table 4. Alkylation of aldehydes with the carbocation 4.
havior of the tropylium cation
arises from a nonideal tempera-
ture effect,[22] a phenomenon
that was recently described in
organocatalytic reactions.[23]
The proposed catalytic cycle
for the reaction is depicted in
Scheme 2. As a first step, we
propose the formation of the
enamine by reaction of the
MacMillan catalyst as a salt
with the corresponding alde-
Entry
R
Product
T [8C]
t [h]
Yield [%][a]
d.r.[b]
ee [%] (major)[c]
ee [%] (minor)[d]
1
2
nC6H13
nC6H13
nC6H13
iPr
iPr
iPr
11a
11a
11a
11b
11b
11b
11c
11c
0
ꢁ25
ꢁ25
0
2
2.5
3
24
21
74
22
22
90
68
13
34
51
41
97
88
4:1
9:1
1.1:1
4:1
4:1
2.3:1
2.3:1
7:3
78
80
22
77
92
71
52
69
2
10
11
64
62
76
16
24
3[e]
4
5
6
7
8
ꢁ25
0
hydes.
The
stoichometric
Bn
Bn
0
ꢁ25
amount of acid (HX) formed
during the reaction is trapped
by 2,6-lutidine (B). Water
formed during the catalytic step
is necessary to the process and
it is a possible nucleophile, able
to react with the carbocations.
As a matter of fact, when the
[a] Yield after chromatographic purification. [b] d.r.=diastereomeric ratio. Determined by 1H NMR spectros-
copy on the crude reaction mixture. The syn/anti ratio was not assigned and is indicated as the major versus
minor diastereoisomer. [c] The enantiomeric excess was evaluated by chiral HPLC analysis. See the Support-
ing Information for details. The enantiomeric excess values are indicated for the major diiastereoisomer.
[d] Enantiomeric excess values for the minor diastereoisomer. [e] The BF4ꢁ salt was used.
tioning that the reaction of 4 with 1-(trimethylsiloxy)cyclo-
hexene gave a low yield of adducts as a mixture of two dia-
stereoisomers in a ratio of 79:21. The simple diastereoselec-
tion obtained in our reaction with enamines formed in situ
was close to the result reported by Mayr.
The simple stereoselection and the enantioselectivity in-
creased when the reaction was carried out at ꢁ258C
(Table 4, entries 2, 5, and 8). Yields of isolated product were
bis-bis(4-methoxy-phenyl)methylium cation, positioned at
point 0 of the Mayrꢀs scale, was reacted with octanal and the
catalyst 5 in the usual reaction conditions, only the corre-
sponding alcohol was isolated. Water (N=5.2 in Mayr
scale)[24] generated during the catalytic cycle reacted very
fast with the unstable carbocation, hampering the reaction
with the enamine.
2050
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Chem. Asian J. 2010, 5, 2047 – 2052