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Table 1
Competition reactions between 4c/n and 7–9
TfO-
TfO- N+
N+
O
NaOH (0.1M)
TfO-
N+
R2
N+
R2
O
5 min
r.t.
R1
R7
O
R7
R1
R1
R7
1 eq.
r.t.
R8
R8
+
+
4
6
5
R9
R1
R9
R1
1 eq.
in solution in CH(D)Cl3
1 eq.
H
H
H
H
O
O
4c (R1 = H, R2 = Me)
5c (R1 = H, R2 = Me) 6c (R8 = H, R9 = Me)
O
7-9
Me
Me
4n ( R1, R2 = Me)
5n ( R1, R2 = Me)
6n ( R8, R9 = Me)
Me
Me
H
Entry
R1, R2
H, Me
Me, Me
Me, Me
H, Me
R8, R9
Ratio 5:6a
H
H
H
H
1
2
3
4
5
4c
4n
4n
4c
4n
H, Meb
Me, Me
H, Meb
H, H
7
8
7
9
9
>95:5c
>95:5
85:15
>95:5c
73:28
6c, 53%a, 75:25b,c
6g, 46%, 75:25
6h, 39%, 75:25
H
O
H
O
H
O
Me, Me
H, H
Me
H
H
H
H
a
b
c
Ratio determined by 1H NMR spectroscopy.
Compound 7 in mixture with 2-methylcyclobut-2-en-1-one (ratio = 1:1).
2-Methylcyclobut-2-en-1-one was 100% recovered.
H
Me
6i, 57%, 75:25
6j, 51%, 75:25
6m - (no reaction with 4m)
a Isolated yield obtained after purification by flash chromatography on silica
gel.
b Diatereoisomeric ratio (endo/exo) determined by integration of the ethylenic
signals in the crude 1H NMR).
TfO-
TfO-
N+
c endo product represented (obtained as a single diastereomer).
O
O
O
N+
Me
Scheme 6. [4+2] cycloaddition reactions between cyclobuteniminium salts 4 and
cyclopentadiene.
H
Me
Me
H
H
Me
Me
Me
H
TfO-
TfO-
TfO-
H
TfO-
8
7
9
4n
4c
N+
N+
N+
N+
H
dienophiles reactivity
1 eq.
+
+
Me
Me
Me
H
Me
r.t.
Scheme 8. Classification of 4-membered ring derivatives regarding their reactivity
in Diels–Alder reaction.
H
H
H
Me
1 eq.
Me
1 eq.
4c
4n
5c
5n
in solution in CDCl3
> 95: 5
showed higher reactivity than methyl cyclobutenone 7 (Table 1,
entry 3). Cyclobuteniminium salts 4c/n were also studied in com-
parison to cyclobutenone 9 which has been previously used by
Danishefsky et al. in Diels–Alder reactions with various dienes
(Table 1, entries 4 and 5).17 To our delight, the [4+2] cycloaddition
reactions with the cyclobuteniminium salts 5c/n were again much
faster than with cyclobutenone 9.
Based on the results of different competition reactions
(Scheme 7, Table 1), a classification of the dienophiles regarding
their reactivity in Diels–Alder has been made and is depicted in
Scheme 8.18
DFT calculations were performed to quantify the difference in
reactivity for the fastest (4c) and slowest (8) reacting dienophiles
as depicted in Scheme 8. Cycloaddition reactions with cyclopenta-
diene (CPD) were modeled using the G09 program package19 at the
M06-2X/6-31+G(d,p)20 level of theory, which is able to account for
non-covalent interactions. The transition state geometries for the
two dienophiles are shown in Figure 3. While the [4+2] cycloaddi-
tion between cyclobutenone 8 and cyclopentadiene is relatively
synchronous, the large difference in critical distances in the
charged cyclobuteniminium 4c case is noteworthy.
The significantly large difference in activation energies (Table 2,
DDGà = 18.2 kcal/mol) reflects the substantial difference in reactiv-
ities for cyclobutenones and cyclobuteniminiums and is consistent
with the experimentally observed outcomes listed in Table 1. The
4c adduct is also thermodynamically more stable than its cyclobu-
tenone 8 counterpart. In a recent study by the same authors,9 [4+2]
cycloaddition barriers for cyclopentadiene and N,N-dimethylcyclo-
buteniminium were reported to have an activation barrier approx-
imately 4 kcal/mol higher than the N-piperidine analogue reported
Scheme 7. Competition reaction between 4c and 4n.
Novel cyclobuteniminium salts 4 were then used as dienophiles
in Diels–Alder reaction with cyclopentadiene (Scheme 6).11,12 To
our delight, the [4+2] cycloaddition proceeded at room tempera-
ture in only five minutes affording bicycles 6c,g–j in moderate
yields after the hydrolysis of the iminium salt. Interestingly, while
the [4+2] cycloaddition reactions with disubstituted-cyclobuteni-
minium salts (R1, R2 – H, Scheme 2) were highly exo selective,9
Diels–Alder reactions with 4 afforded endo cycloadduct as the
major isomer (d.r. = 75:25, Scheme 6). It is also important to men-
tion that the two approaches (endo/exo) are perfectly diastereose-
lective (d.r. > 98:2). As previously observed, no reaction occurred
with the cyclobuteniminium salt bearing a trisubstituted olefin
(4m) even with longer reaction time (48 h) or higher temperature
(50 °C).
In order to study the influence of the a
-substitution (R1, R2) on
the reactivity of the cyclobuteniminium salt in Diels–Alder reac-
tion, a competition reaction was performed between methyl-cyclo-
buteniminium salt 4c and dimethyl-cyclobuteniminium salt 4n
(Scheme 7).9 Interestingly, cyclopentadiene was totally consumed
by 4c in few minutes and no trace of cycloadduct 5n was detected
in the crude 1H NMR (5c/5n = 100:0).
Cyclobuteniminium salts 4c/n were then compared to their cyc-
lobutenone analogues 7/913 (Table 1).14 Competition reactions
between 4c and 715 as well as between 4n and 816 clearly demon-
strate the superiority of the iminium derivatives in term of reactiv-
ity (Table 1, entries 1 and 2). Even dimethyl-cyclobuteniminium 4n