to our knowledge the stereoselective construction of complex
polycyclic ring systems of generic structure 1 in Scheme 1
Scheme 1. Nitro-Mannich/Lactamization Cascade for the
Construction of Multicyclic Piperidinone Derivatives
Figure 2. Nitro ester and cyclic imine starting materials.
via reaction of cyclic imines 28 with γ-nitro esters 39 has
yet to be reported.
measuring conversion after an arbitrary 24 h period. The
results are presented in Table 1. At elevated temperatures in
As a range of procedures for the preparation of cyclic
imines are known and as the nitro esters can be readily
constructed via Michael addition reactions, a powerful
reaction sequence to architecturally complex piperidine ring-
containing multicyclic structures emerges that could be useful
in both library synthesis and total synthesis alike. Attracted
by the simplicity and potential synthetic utility of the method,
we began our investigations and herein describe the findings.
Initially, feasibility studies were performed on a repre-
sentative nitro ester 3a (1 equiv) and cyclic imine 2a (2
equiv, Figure 2). These were reacted in solvents ranging from
apolar aprotic to polar protic and reactivity assessed by
Table 1. Feasibility and Optimization Studies in the
Nitro-Mannich/Lactamization Cascade Using 3a and 2a
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entry
solvent
temp
conversion
yield
dr
1
2
3
4
5
6
7
8
hexane
toluene
THF
MeCN
CHCl3
EtOH
MeOH
H2O
reflux
70 °C
reflux
70 °C
reflux
70 °C
reflux
RT
∼0
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
4%
10%
10%
4%
8%
10%
4%
61%
∼100%
11%
9
H2O
H2O
neat
70 °C
70 °C
70 °C
42%
76%
-
>99:1
>99:1
-
10a
11
a Results after 48 h.
(7) (a) Hynes, P. S.; Stranges, D.; Stupple, P. A.; Guarna, A.; Dixon,
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Commun. 2005, 4481. See also: (c) Okino, T.; Hoashi, Y.; Takemoto, Y.
J. Am. Chem. Soc. 2003, 125, 12672. (d) Li, H.; Wang, Y.; Tang, L.; Deng,
L. J. Am. Chem. Soc. 2004, 126, 9906. (e) McCooey, S. H.; Connon, S. J.
Angew. Chem., Int. Ed. 2005, 44, 6367.
aprotic solvents such as hexane, toluene, tetrahydrofuran,
acetonitrile, and chloroform, little or no conversion to the
desired product 1a was observed (entries 1-5). The polar
protic solvents ethanol and methanol at elevated temperatures
were then investigated, and again only low conversions were
obtained (8 and 10%, respectively, entries 6 and 7). Surprised
by the significant difference between these results and those
from our previous studies,5b we then turned to water as a
reaction solvent. Pleasingly, at room temperature, a small
amount of conversion was observed. At 70 °C for 24 h, a
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H.; Strosberg, A. M. J. Med. Chem. 1983, 26, 1426.
(9) For the synthesis of 3a and 3b, see Supporting Information.
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