Generally, the nucleophilic attacks by the â-keto esters
occur at their R-position.7 There are many such reactions.
For example, known as the Knoevenagel condensation,8 the
reactions of â-keto esters and aldehydes give the unsaturated
keto esters that are R-adducts of the â-keto esters. The most
previously reported MCRs using â-keto esters also afford
the R-adducts.6,9 Only in few cases10 were γ-adducts obtained
in the reaction of aldehydes and â-keto esters, but R-alkylated
â-keto esters were used in their cases. No examples of
γ-adducts using R-unsubstituted â-keto esters are known in
MCRs, to the best of our knowledge. In general, the control
of the reaction at the γ-position is difficult, and it is necessary
to prepare dianions.11 In our reaction, the γ-adducts are
produced without preparing dianions even using R-unsub-
stituted â-keto esters. Furthermore, the produced seven-
membered ring compounds have both secondary amine and
enamino ester units, which would serve in further function-
alizations to produce molecular diversity. Therefore, they
would be expected as new skeletons in drug discovery.
As part of our studies about the synthetic application of
the aminals prepared from aldehydes and diamines,12 we
realized the unexpected reactivity of the â-keto ester. Thus,
the addition of methyl acetoacetate 2a (1.0 equiv) to a
mixture of benzaldehyde 1a and ethylenediamine (1.0 equiv)
under acidic conditions, p-TsOH‚H2O (0.1 equiv), produced
the seven-membered ring compound 3a, which was the
γ-adduct of 2a. The C-C double bond of 3a was determined
as cis because the signal of NH appears at 8.91 ppm in the
1H NMR chart for intramolecular hydrogen bonding with
the carbonyl group (Scheme 1). We first expected the
The reaction conditions were studied using benzaldehyde
1a, ethylenediamine (1.0 equiv), and methyl acetoacetate 2a
(1.0 equiv). The results are shown in Table 1. For entries
Table 1. Optimization of the Reaction Conditions
entry
solvent
acid
time
yielda
1
2
3
4
5
6
7
8b
toluene
DCE
DCM
DCE
-
-
-
-
p-TsOH‚H2O
-
-
TFA
PPTS
AcOH
CSA
3 days
20 h
-
-
-
-
-
-
39%
59%
ndc
54%
48%
ndc
56%
59%
p-TsOH‚H2O
a
b
c
Isolated yield. All reagents were added successively. nd ) not
determined on TLC.
1-7, 1a and ethylenediamine were stirred for 1 h. 2a and
acid were then added to the resulting mixture, and the
solution was heated under reflux. For entries 1-3, the effect
of the reaction solvent was examined in the presence of
p-TsOH‚H2O (0.1 equiv). The reaction proceeded in moder-
ate yield in toluene (Table 1, entry 1). When 1,2-dichloro-
ethane (DCE) was used as the solvent, a better result was
obtained (Table 1, entry 2). On the other hand, 3a was not
obtained in dichloromethane (DCM) due to the low reaction
temperature (Table 1, entry 3). We next studied the acid
catalysts, trifluoroacetic acid (TFA), pyridinium p-toluene-
sulfonate (PPTS), AcOH, and camphorsulfonic acid (CSA),
in DCE (Table 1, entries 4-7). These acids, except for
AcOH, were effective and produced 3a in moderate yields.
The other solvents (THF and CH3CN) and other acids (TfOH,
Tf2NH, BF3‚Et2O, and Yb(TfO)3) were not effective. During
the reaction process, the successive addition of 1a, ethyl-
enediamine, 2a, and p-TsOH‚H2O (0.1 equiv) gave the same
good result (Table 1, entry 8). We then determined the
conditions in entry 8 of Table 1 as the optimized conditions.
Under the optimized conditions, the reactions of various
aldehydes, ethylenediamine, and methyl acetoacetate 2a in
the presence of p-TsOH‚H2O (0.1 equiv) were examined
(Table 2). Various aromatic aldehydes are available for this
reaction (Table 2, entries 1-8).
Scheme 1
formation of the R-adducts 4a or 4b from the reactivity of
the â-keto esters as described above. This unexpected
outcome was very curious. We then studied the reaction in
detail.
(7) For a review, see: Benetti, S.; Romagnoli, R.; Risi, C. D.; Spalluto,
G.; Zanirato, V. Chem. ReV. 1995, 95, 1065-1114.
(8) Jones, G. Org. React. 1967, 15, 204-599.
(9) For a review, see: (a) Simon, C.; Constantieux, T.; Rodriguez, J.
Eur. J. Org. Chem. 2004, 4957-4980. For recent studies, see: (b) Lie´by-
Muller, F.; Constantieux, T.; Rodrigez, J. J. Am. Chem. Soc. 2005, 127,
17176-17177. (c) Lie´by-Muller, F.; Simon, C.; Imhof, K.; Constantieux,
T.; Rodrigez, J. Synlett 2006, 1671-1674
(10) Rodoriguez’s group reported multicomponent selective R,γ-difunc-
tionalization of cyclic 1,3-dicarbonyl compounds via reversible R-aldol
reaction: Habib-Zahmani, H.; Hacini, S.; Charonnet, E.; Rodoriguez, J.
Synlett 2002, 1827-1830. And related work: Charonnet, E.; Filippini, M.-
H.; Rodrigez, J. Synthesis 2001, 788-804.
Although the substitution of the electron-donating methoxy
group decreased the yield (Table 2, entry 1), the substitutions
(11) For examples, see: (a) Langer, P.; Bellur, E. J. Org. Chem. 2003,
68, 9742 -9746. (b) Lygo, B. Tetrahedron 1995, 51, 12859-12868. (c)
Jannet, H. B.; Mourabit, A. Al; Gateau-Olesker, A.; Marazano, C.; Mighri,
Z. Tetrahedron: Asymmetry 1999, 10, 2381-2386.
(12) (a) Fujioka, H.; Murai, K.; Ohba, Y.; Hiramatsu, A.; Kita, Y.
Tetrahedron Lett. 2005, 46, 2197-2199. (b) Fujioka, H.; Murai, K.; Ohba,
Y.; Hirose, H.; Kita, Y. Chem. Commun. 2006, 832-834. (c) Fujioka, H.;
Murai, K.; Kubo, O.; Ohba, Y.; Kita, Y. Tetrahedron 2007, 63, 638-643.
1688
Org. Lett., Vol. 9, No. 9, 2007