Asymmetric organocatalytic Michael-α-amination sequence for the construction of a quaternary stereocenter

Article abstract of DOI:10.1039/c0ob00751j

Combination of secondary and primary amine-catalyzed organocascade Michael-α-amination is described. This sequence afforded α-hydrazino aldehydes bearing a quaternary stereocenter with high yield and excellent stereoselectivity.

Full text of DOI:10.1039/c0ob00751j

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Asymmetric organocatalytic Michael–a-amination sequence for the
construction of a quaternary stereocenter†
Alaric Desmarchelier, Je´roˆme Marrot, Xavier Moreau* and Christine Greck*
Received 20th September 2010, Accepted 18th November 2010
DOI: 10.1039/c0ob00751j
Combination of secondary and primary amine-catalyzed
organocascade Michael–a-amination is described. This se-
quence afforded a-hydrazino aldehydes bearing a quaternary
stereocenter with high yield and excellent stereoselectivity.
Introduction
Organocascade catalysis has emerged as a powerful strategy for
the construction of highly functionalized molecules from simple
Scheme 1 Organocatalytic Michael–a-amination sequence.
achiral starting materials.1 Taking advantage of the different
modes of activation allowed in organocatalysis, a single catalyst or
a combination of catalysts2 is able to achieve two or more reactions
documented in the literature. The choice of the catalytic system
with a high degree of stereocontrol. Until recently, this field
was driven by the overall efficiency of both reactions in terms
was dominated by the use of aminocatalysis3 and organocascade
of low catalyst loading and availability, short reaction time and
high level of stereocontrol. Primary10 and secondary amines are
able to catalyze the Michael addition of aldehydes to nitroalkenes
whereas a-amination of hindered aldehydes proved to be difficult
with a pyrrolidine core11 (50 mol% catalyst loading is generally
used for this transformation). Preliminary studies12 revealed that a
combination of diphenylprolinol silyl ether 1 used in the conditions
described by Hayashi13 (propionaldehyde (10 eq.), nitrostyrene (1
eq.), 1 (10 mol%) in hexane) and 9-amino(9-deoxy)epi-cinchonine
2 used in the conditions described by Melchiorre14 (aldehyde (1
eq.), DBAD (1.5 eq.), 2 (20 mol%) in CHCl3) was an efficient
catalytic system for a sequential process (Scheme 2, eqn (1)). The
challenge was then to optimize theses conditions toward a one
pot procedure by lowering the amount of starting aldehyde and
catalyst loading and homogenize the solvent conditions. In this
way, Michael addition of propionaldehyde (1.2 eq.) to nitrostyrene
(1 eq.) was achieved by using only 5 mol% catalyst 1 in CHCl3 at
0 ◦C. After completion of the reaction, the electrophilic nitrogen
reagent (DBAD, 1.5 eq.), TFA (15 mol%) and catalyst 2 (5 mol%)
were added to the same vessel (Scheme 2, eqn (2)). The expected
product was obtained as a single diastereoisomer15 in 80% yield
and 96% ee.
sequences involving iminium/enamine activation were the most
reported.4 By contrast, enamine/enamine activation, which would
afford a,a disubstituted aldehydes or aldehydes containing a
quaternary stereogenic center,5 has received little attention. For
example, List and co-workers6 have reported a double Mannich
reaction of acetaldehyde catalyzed by proline. Enders and co-
workers7 have described a sequence made up of a Michael addition
of aldehydes to nitroalkenes followed by an intramolecular alkyla-
tion leading to substituted cyclopentanes. Herein, we would like to
present a new example of double enamine activation of aldehydes
outlinedinScheme1. We envisionedareaction sequenceconsisting
of a Michael addition of aldehydes to nitroalkenes followed by
subsequent electrophilic a-amination catalyzed by a combination
of secondary and primary amines.
Results and discussion
Organocatalytic Michael addition of carbonyl compounds to
nitroolefins8 and a-amination of aldehydes and ketones9 are well
With these conditions in hand, the scope of the sequence was
surveyed using various nitroalkenes (Table 1). Reactions with
aromatic nitroolefins afforded the corresponding a-hydrazino
aldehydes bearing a quaternary stereocenter with high yields
(73–90%) and excellent stereoselectivities. In each case, a sin-
gle diastereoisomer is observed with high enantioselectivity
Institut Lavoisier de Versailles, UMR CNRS 8180, Universite´ de Versailles-
Saint-Quentin-en-Yvelines, 45, Avenue des Etats-Unis, 78035, Versailles
Cedex, France. E-mail: moreau@chimie.uvsq.fr, greck@chimie.uvsq.fr
† Electronic supplementary information (ESI) available: Experimental
details, NMR spectra and HPLC traces. CCDC reference number 784199.
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c0ob00751j
994 | Org. Biomol. Chem., 2011, 9, 994–997
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Table 1 Organocatalytic Michael addition–a-amination sequence of propionaldehyde with different nitroalkenes
Entry Conditions
Product
Yielda (ee)b Entry Conditions
Product
Yielda (ee)b
85% (98%)
1
Michael (0 ◦C, 4 h)
90% (96%)
5
Michael (0 ◦C, 5 h)
Amination (r.t., 30 h)
Amination (r.t., 70 h)
2
Michael (0 ◦C, 4 h)
Amination (r.t., 65 h)
73% (96%)
6
Michael (0 ◦C, 4 h)
Amination (r.t., 140 h)
81% (97%)
3
4
Michael (0 ◦C, 6 h)
Amination (r.t., 25 h)
85% (96%)
85% (97%)
7
8
Michael (0 ◦C, 4 h)
Amination (r.t., 90 h)
85% (98%)
76% (96%)
Michael (0 ◦C, 8 h)
Amination (r.t., 22 h)
Michael (0 ◦C, 4 h)c
Amination (r.t., 88 h)
a Isolated yield. b Determined by chiral HPLC analysis. c 1 (10 mol%) and 2 (5 mol%) were used for the reaction.
Scheme
2
Optimized conditions for the one pot sequence
Michael–a-amination sequence.
Scheme 3 ORTEP diagram of 4.
(96–98% ee).15 Electron-rich and electron-deficient aryl groups
and the position of the substituent (i.e. para or meta) on the
aromatic ring provided the same results. The limitation of the
present methodology was found when butyraldehyde was used
instead of propionaldehyde. In this case, the amination step
was very slow and only 50% conversion was observed after
a week. The determination of the absolute and relative con-
figuration was achieved by means of an X-ray crystallographic
analysis of compound 416 (Scheme 3). Suitable crystals were
obtained by using DtBAD instead of DBAD as the electrophilic
nitrogen source for the amination step of the known com-
pound 3.13
A
syn relationship between Me and Ph groups was
observed and it was concluded that 4 was di-tert-butyl-1-
((2S,3S)-2-methyl-4-nitro-1-oxo-3-phenylbutan-2-yl)hydrazine-
1,2 dicarboxylate.17
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Table 2 a-Amination of a-disubstituted aldehyde 3 with different pri-
mary amines
of aldehydes. This reaction generates a-hydrazino aldehydes
bearing a quaternary stereogenic center with high yields and
excellent stereoselectivities.
Further investigations into this reaction sequence, including its
synthetic applications, are presently underway.
Entry
1b
Primary amine catalyst
Ratio 5/6a
>19/1
Yield
88%
Acknowledgements
The authors thank the MENRT, CNRS and the Univer-
sity of Versailles-St-Quentin-en-Yvelines for a grant (A.D.)
and financial support. We also thank Prof. Prim for helpful
discussions.
2
3
1/1
86%
89%
3.4/1
References
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4
1/1.9
87%
2 For a general review, see (a) J. Zhou, Chem.–Asian J., 2010, 5, 422. For
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1
a Determined by H NMR on the crude product. b 5 mol% of catalyst 7
was used for the reaction.
Then, we envisioned synthesizing the diastereomer of com-
pound 5 by simply changing catalyst 2 for its pseudo enantiomer
catalyst 7 (Table 2, entry 1). Surprisingly, these conditions afforded
the same product 5 with similar results as described above (Table 1,
entry 1).
Finally, we screened different alkyl benzylamines as catalysts
for the C–N bond forming step. As expected, benzylamine led
to a 1/1 mixture of stereoisomer 5 and 6 (entry 2). When (R)-
a-methylbenzylamine was used to promote the reaction, the
diastereomeric ratio increased to 3.4/1 in favour of aldehyde 5
(entry 3). If the enantiomer (S)-a-methylbenzylamine was used as
the catalyst, we observed the formation of aldehyde 6 as the major
diastereomer (5/6: 1/1.9; entry 4). The diastereomeric mixture was
separated by flash chromatography on silica gel and compound 6
was isolated in 52% yield and 96% ee.
To improve the synthetic scope of this methodology, we
transformed the resulting aldehyde compound. As illustrated
in Scheme 4, the aldehyde moiety was oxidized under smooth
conditions (KH2PO4, NaClO2 and H2O2) and esterified to afford
the a-hydrazino ester in 50% yield.
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Jacobsen, Angew. Chem., Int. Ed., 2006, 45, 6366; (b) S. H. McCooey
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Scheme 4
Conclusion
12 In our hands, primary amine-catalyzed Michael addition gave only
poor results.
In summary, a new organocatalytic Michael–a-amination se-
quence has been developed based on a double enamine activation
13 Y. Hayashi, H. Gotoh, T. Hayashi and M. Shoji, Angew. Chem., Int.
Ed., 2005, 44, 4212.
996 | Org. Biomol. Chem., 2011, 9, 994–997
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3
-1
˚
˚
14 P. Galzerano, F. Pesciaioli, A. Mazzanti, G. Bartoli
and P. Melchiorre, Angew. Chem., Int. Ed., 2009, 48,
7892.
A, b = 99.962(11), V = 2482.5(11) A ; Z = 4; m = 0.088 mm ; 136 829
reflections measured at RT; independent reflections: 4347 [4107 Fo > 4s
(Fo)]; data were collected up to a 2Hmax value of 50◦ (99.6% coverage).
Number of variables: 287; R1 = 0.0659, wR2 = 0.1933, S = 1.216; highest
15 Diastereomeric excesses were determined by 1H NMR on the crude
product and enantiomeric excesses were determined by chiral HPLC
using AS-H or OD-H columns.
residual electron density 0.532 e A-3 (all data R1 = 0.0861, wR2 = 0.2158).
˚
CCDC 784199.
16 Crystal data: C21H31N3O7, Mw = 437.49, monoclinic, space group
17 This compound was also synthesized according the one-pot procedure
in 85% yield.
˚
˚
P21/c; dimensions: a = 10.158(3) A, b = 14.069(4) A, c = 17.637(4)
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Org. Biomol. Chem., 2011, 9, 994–997 | 997
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