Bipiperidine-Mediated Michael Addition
TABLE 1. Michael Addition of Propionaldehyde 5a to
trans-ꢀ-Nitrostyrene 6a Catalyzed by 2,2′-Bipiperidine Derivatives
1-3 and 3,3′-Bimorpholine 4
entry
catalyst
BP (1)
MeBP (2a)
iPrBP (2b)
iPrBP TFA (3) 9 d
iPrBM (4) 24 h
time yielda (%) dr (syn/anti)b eeb (syn) (%)
FIGURE 2. Organocatalysts 1-4.
1
32 h
2 h
45
94
91
52
90
60:40
76:24
91:9
70
-59
91
2c
3
1 h
The only difference in the structures of these catalysts lies in
the ꢀ-position of the bridging bond between two heterocycles:
there is an oxygen atom in bimorpholine and a methylene group
in bipiperidine in that position. However, this subtle change in
the structure of the catalyst makes the synthesis of BP easy
and straightforward from commercial 2,2′-dipyridyl in one step.7
4
85:15
82:18
84
74
5d
a Isolated yield after purification by column chromatography on silica
gel. b Determined by chiral HPLC. Relative (syn) and absolute config-
urations determined by comparison with literature data. c (2S,2′S)-MeBP
was used. d Reference 5.
Results and Discussion
Indeed, the decrease of temperature to 0 °C increased enanti-
oselectivity to 93% (Table 2, entry 2), and at -25 °C, we
observed the highest ee, 96% (Table 2, entry 3). Furthermore,
the diastereoselectivity of the reaction showed the same trend.
Even though the catalyst loading was decreased to 5 mol % the
product formed in 4 h with no change in enantioselectivity
(Table 2, entry 4). The reactivity and stereoselectivity of the
catalyst 2b were much higher than in the case of the corre-
sponding N-iPr-bimorpholine 4 (Table 2, entry 5). Michael
addition with moderately sterically hindered aldehydes, like
valeraldehyde (Table 2, entry 6) and isovaleraldehyde (Table
2, entry 8), proceeded with good ee and dr. Phenylacetaldehyde
was quite reactive but afforded a product with low selectivity
(dr 62:38 and ee 37%) (Table 2, entry 10). A clear dependence
between reactivity and steric hindrance was observedsa bulky
isobutyraldehyde afforded only 14% yield after a 7 day reaction
with low enantioselectivity (Table 2, entry 11). There is a drastic
difference in the reactivities of bimorpholine and bipiperidine
catalysts. The reaction time needed to obtain a comparable
conversion of the starting material was several times longer
when using the morpholine derivative than the piperidine
derivative (Table 2, entries 6, 7 and 8, 9). The enamine
intermediate derived from BP is clearly more nucleophilic10 and
reacts faster. The scope of the carbonyl compounds in this
reaction was limited to aldehydes. Cyclohexanone gave only
traces of the product after 9 days when the reaction was run at
an elevated temperature (60 °C).
Herein, we present the results of Michael addition of
aldehydes to nitroolefins catalyzed by (2R,2′R)-bipiperidine
derivatives 1-3 and bimorpholine derivative 4 (Figure 2).
We have reported the preparation of N-iPr-BP 2b.8 The same
methodology based on the aminal formation with formaldehyde
and its reduction with sodium borohydride was applied to the
synthesis of Me-BP 2a in the present study. In order to establish
the most reactive and selective catalyst, we studied 2,2′-
bipiperidine 1 as well as its three derivatives (2a, 2b, 3) in the
Michael addition of the enamine intermediates formed from
propionaldehyde to trans-ꢀ-nitrostyrene (Table 1). Two N-
monosubstituted piperidinesssterically less demanding methyl
compound (2a) and bulkier isopropyl compound (2b)swere
used and compared with N-iPr-bimorpholine 4.
The reaction was conducted in the presence of 15 mol % of
the catalyst in chloroform at room temperature. Methyl-
substituted bipiperidine 2a showed high reactivity but moderate
selectivity, and the reaction was complete in 2 h (Table 1, entry
2). The bulkier iPr group at the nitrogen atom made the catalyst
2b more selective and more reactive (Table 1, entry 3). It was
found that catalyst 2b was more efficient than the corresponding
bimorpholine derivative 4 (Table 1, entry 5).5 It is known that
Brønsted acid additive has a substantial influence on the
selectivity of Michael addition to nitrostyrenes.9 Therefore,
monosalt 3 was synthesized from trifluoroacetic acid and N-iPr-
BP 2b, and it turned out to be quite a selective catalyst, although
a very unreactive one. The reaction time increased up to 9 days,
affording the product with only a moderate yield (Table 1, entry
4). Thus, N-iPr-BP 2b was the catalyst of choice for investigat-
ing the addition of different aldehydes to ꢀ-nitrostyrene (Table
2).
To complete the study, we investigated several Michael
acceptors in the reaction with propionaldehyde in the presence
of a more reactive and selective catalyst 2b (Table 3). The
electron-donating methoxy group in the para position of the
phenyl ring made the double bond less reactive (Table 3, entry
2). Nitrostyrene with the unsubstituted phenyl ring as well as
the phenyl rings with electronegative substituents (4-Br and
4-CF3O group) showed high reactivity in the presence of
N-iPrBP and afforded products in a very high yield (>90%,
Table 3, entries 1, 3, and 4). The substituents on the phenyl
ring did not influence substantially enantio- or diastereoselec-
tivity of the reaction: ee ranged from 88 to 91%, dr 84:16 to
91:9. The decrease in the temperature did not improve the
stereoselectivity (Table 3, entry 5).
The smallest, less sterically hindered propionaldehyde was
the most reactive substrate toward Michael addition, resulting
in a product of a high yield in just 1 h at room temperature
(Table 2, entry 1) with 91% ee. The high reactivity of the
catalyst allowed us to investigate the reaction at lower temper-
ature in an attempt to increase enantio- and diastereoselectivity.
(7) Krumholz, P. J. Am. Chem. Soc. 1953, 75, 2163.
(8) Laars, M.; Kriis, K.; Kailas, T.; Mu¨u¨risepp, A.-M.; Pehk, T.; Kanger,
T.; Lopp, M. Tetrahedron: Asymmetry 2008, 19, 641.
(9) (a) Mase, N.; Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka, F., III J. Am.
Chem. Soc. 2006, 128, 4966. (b) Pansare, S. V.; Pandya, K. J. Am. Chem. Soc.
2006, 128, 9624. (c) Ishii, T.; Fujioka, S.; Sekiguchi, Y.; Kotsuki, H. J. Am.
Chem. Soc. 2004, 126, 9558. (e) Bolm, C.; Rantanen, T.; Schiffers, I.; Zani, L.
Angew. Chem., Int. Ed. 2005, 44, 1758. (f) Alexakis, A.; Andrey, O. Org. Lett.
2002, 4, 3611.
(10) (a) Kempf, B; Hampel, N.; Ofial, A. R.; Mayr, H. Chem. Eur. J. 2003,
9, 2209. (b) Mayr, H.; Ofial, A. R. J. Phys. Org. Chem. 2008, 21, 584.
J. Org. Chem. Vol. 74, No. 10, 2009 3773