There is still a large demand for the development of new
efficient Michael acceptors in order to extend the scope of
this fascinating reactivity and to better understand the
mechanism of reaction. Therefore, we directed our efforts
toward the study of easily accessible 1,3-activated dienes
with a focus on 4-substituted 1,3-bis(alkyl carboxylate)
butadienes that can be simply obtained through a single
step Knoevenagel condensation from commercial gluta-
conic esters and aldehydes, although this reaction leads to
dienes as mixtures of stereoisomers.6
We began our investigation using 1a as a single isomer
model diene and isovaleraldehyde (Table 1). This test
reaction was carried out in the presence of 20 mol % of
proline-based organocatalysts 3aꢀd and at low concentra-
tion of the diene (Table 1).
conversion and moderate enantioselectivity was observed
with the same class of organocatalyst 3b (entry 2). Using R,
R-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether 3c
(entry 3), 48% conversion and excellent 99% ee was
achieved, while the strongly electron-withdrawing 3,5-bis-
(trifluoromethyl)aryl-substituted catalyst 3d8 did not pro-
duce any conversion (entry 4). After this short screening of
aminocatalysts, the reaction conditions were optimized
using catalyst 3c. A drastic decrease of reactivity was
observed in apolar solvents such as toluene (entry 5), while
a 5% v/v aqueous solution of ethanol appeared to be the
best media both in terms of conversion and stereoselectiv-
ity (entry 6). Unfortunately, due to increased formation of
aldehyde byproducts this solvent mixture was not further
used. Acid additives such as BzOH or AcOH had unfavor-
able consequences on the reaction rate (entries 7 and 8).
Surprisingly, when substrate 1a was employed as mixture
of isomers 4E/4Z in combination with 3c in CHCl3 no
negative impact on stereoselectivity was recorded, and the
conversion was slightly increased (entry 9). This last result
opened the opportunity to use stereoisomeric mixture of
4-aryl-substituted 1,3-bis(alkyl carboxylate) butadienes as
substrates for this reaction, avoiding time-consuming and
solvent spending separations. Finally, quantitative transfor-
mation of 1a was achieved by increasing the concentration of
the substrate (0.5 M) and the reaction time (entry 10) while
lowering the amount of aldehyde to 4 equiv.
Table 1. Screening of Organocatalysts and Optimization of the
Reaction Conditionsa
Having these optimized conditions in hand, we started
exploring the scope and the limitation of this transformation.
time
(h)
convb eec
entry cat.
solvent
CHCl3
additive
none
none
none
none
none
(%)
(%)
Table 2. Scope of Aldehydes for Organocatalytic Annulationa
1
3a
3b
3c
3d
3c
3c
3c
3c
3c
3c
48
48
48
48
48
48
48
48
48
45
36
90
49
2
3
CHCl3
CHCl3
CHCl3
toluene
48 >99
4
5
0
12
70
34
33
nd
nd
96
98
94
6
7
8
H2O/EtOHd none
CHCl3
CHCl3
CHCl3
CHCl3
BzOH (0.4 equiv)
AcOH (0.4 equiv)
none
9e
10f
60 >99
>99 >99
entry aldehyde time (h)
yieldb (%)
48 77, 4b
eec (%)dr (trans/cis)d
120
none
a Reaction conditions (entry 1ꢀ9): 20 mol % of catalyst, low con-
centration of the substrate (0.15 M), and 10 equiv of isovaleraldehyde at
room temperature. b Determined by 1H NMR on the crude mixture.
c Determined by chiral SFC. d Relative ratio = 20/1. e 1a as E/Z mix-
ture = 40/60. f Reaction conditions: 20 mol % of catalyst, concentration
of the substrate (0.5 M), and 4 equiv of isovaleraldehyde and 1a as E/Z
mixture = 40/60.
1
R = iPr
99
ꢀ99
99
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
2.7/1
2e R = iPr
72 95, (ent)4b
72 95, 4c
3
4
5
6
7
8
R = Et
R = nPr
96 92, 4d
>99
99
R = nPent
R = Bn
120 74, 4e
72 76, 4f
97.7
(S)- citronellal
rac-citronellalf
72 92, 4g
72 (conv = 81%) 4g
Aminal-pyrrolidine (APY) catalyst 3a, recently devel-
oped by our group,7 in CHCl3 led to optically active
cyclohexa-1,3-diene 4a with promising 45% conversion
and high stereocontrol (90% ee, entry 1). Slightly lower
a Reaction conditions: 20 mol % of catalyst 3c, concentration of the
substrate (0.5 M), 4 equiv of isovaleraldehyde and 1b as E/Z mixture =
73/27. b Isolated yield. c Determined by chiral SFC. d Determined by 1H
NMR analysis. e (R)-3c as catalyst, product 4b (R,R). f 8 equiv of rac-
citronellal was used.
(6) (a) Hourcade, S.; Ferdenzi, A.; Retailleau, P.; Mons, S.; Marazano,
C. Eur. J. Org. Chem. 2005, 7, 1302. (b) Henrich, F. Chem. Ber. 1902, 35 (2),
1663.
(7) (a) Quintard, A.; Bournaud, C.; Alexakis, A. Chem.;Eur. J.
2008, 14, 7504. (b) Quintard, A.; Belot, S.; Marchal, E.; Alexakis, A. Eur.
J. Org. Chem. 2010, 927. (c) Quintard, A.; Alexakis, A. Chem. Commun.
2010, 46, 4085. (d) Quintard, A.; Lefranc, A.; Alexakis, A. Org. Lett.
2011, 13, 1540. (e) Quintard, A.; Langlois, J.-B.; Emery, D.; Mareda, J.;
(8) On the applications of catalysts 3c and 3d: (a) Marigo, M.; Wabnitz,
T. C.; Fielenbach, D.; Jorgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 794.
(b) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed.
ꢀ
2005, 44, 4212. (c) Franzen, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.;
Jorgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296. (d) Xu, L. W.; Li, L.;
Shi, Z.-H. Adv. Synth. Catal. 2010, 352, 243.
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Guenee, L.; Alexakis, A. Chem.;Eur. J. 2011, 17, 13433.
B
Org. Lett., Vol. XX, No. XX, XXXX