Bronsted-acid-catalyzed activation of nitroalkanes: A direct enantioselective aza-henry reaction

Article abstract of DOI:10.1021/ol8003589

A direct asymmetric organocatalytic aza-Henry reaction has been developed in which a new bifuctlonal Bronsted-acid-catalyzed activation of nitroalkanes provides an efficient access to α,β-diamino acids with high dia- and enantioselectivities under mild and base-free reaction conditions.

Full text of DOI:10.1021/ol8003589

ORGANIC
LETTERS
2008
Vol. 10, No. 9
1731-1734
Brønsted-Acid-Catalyzed Activation of
Nitroalkanes: A Direct Enantioselective
Aza-Henry Reaction
Magnus Rueping* and Andrey P. Antonchick
Degussa Endowed Professorship, Institute of Organic Chemistry and Chemical
Biology, UniVersity Frankfurt, Max-Von-Laue Strasse 7, 60438 Frankfurt am Main,
Germany
M.rueping@chemie.unifrankfurt.de
Received February 17, 2008
ABSTRACT
A direct asymmetric organocatalytic aza-Henry reaction has been developed in which a new bifuctional Brønsted-acid-catalyzed activation of
nitroalkanes provides an efficient access to r,ꢀ-diamino acids with high dia- and enantioselectivities under mild and base-free reaction conditions.
The addition of nitroalkanes to aldimines, the aza-Henry
reaction, represents an important C-C coupling reaction
which can result in the formation of two neighboring,
nitrogen containing, stereocenters.1 These valuable reactions
represent not only a simple route to numerous chiral synthetic
building blocks but also provide efficient access to vicinal
diamines2 and R-carbonyl compounds.3
Attempts to achieve asymmetric variants of the nitro-Mannich
reaction have previously been made using chiral metal com-
plexes4 or metal free catalysts5 in combination with various
aromatic aldimines and R-amidosulfones which gave the
corresponding 2-nitroamines with good yields and selec-
tivities.
kanes with R-iminoesters has not previously been described
although the corresponding R,ꢀ-diamino acids are of great
biological significance and are the basis for numerous natural
products.6 This is often due to the reaction conditions being
too basic resulting in the loss of enantio- and diastereoselectivity.
On the basis of these facts we decided to examine a direct
Brønsted-acid-catalyzed enantioselective aza-Henry reaction
(eq 1).
(1)
This would not only be the first example of such a reaction
but it would also be a conceptionally new approach insofar
However, despite these interesting results it is surprising that
an asymmetric organocatalytic aza-Henry reaction of nitroal-
(5) (a) Metal-free enantioselective variants with thiourea: Okino, T.;
Nakamura, S.; Furukawa, T.; Takemoto, Y Org. Lett. 2004, 6, 625. (b)
Yoon, T. P.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2005, 44, 466. (c)
With chincona alcaloids: Palomo, C.; Oiarbide, M.; Laso, A.; Lopez, R.
J. Am. Chem. Soc. 2005, 127, 17622. (d) Robak, M. T.; Trincado, M.;
Ellman, J. A J. Am. Chem. Soc. 2007, 129, 15110. (e) With amidines:
Nugent, B. M.; Yoder, R. A.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126,
3418. (f) Hess, A. S.; Yoder, R. A.; Johnston, J. N. Synlett 2006, 147. (g)
Singh, A.; Yoder, R. A.; Shen, B.; Johnston, J. N J. Am. Chem. Soc. 2007,
129, 3466. (h) The nitro-Mannich reaction in neat nitropropane (pKa
(propane-nitronic acid) ) 4.6) was accelerated by the addition of substo-
ichiometric amounts of AcOH (pKa ) 4.7) : Anderson, J. C.; Blake, A. J.;
Howell, G. P.; Wilson, C. J. Org. Chem. 2005, 70, 549.
(1) (a) Westermann, B. Angew. Chem., Int. Ed. 2003, 42, 151. (b) Arend,
M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044.
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37, 2581.
(3) Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017.
(4) (a) Metal-catalyzed asymmetric aza-Henry reaktions with ytterbium:
Yamada, K.; Harwood, S. J.; Gro¨ger H., Shibasaki; M, Angew. Chem., Int.
Ed. 1999, 38, 3504. (b) Aluminium: Yamada, K.; Moll, G.; Shibasaki, M.
Synlett 2001, 980. (c) Copper: Knudsen, K. R.; Risgaard, T.; Nishiwaki,
N.; Gothelf, K. V.; Jørgensen, K. A. J. Am. Chem. Soc. 2001, 123, 5843.
(d) Nishiwaki, N.; Knudsen, K. R.; Gothelf, K. V.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2001, 40, 2992.
10.1021/ol8003589 CCC: $40.75
Published on Web 04/08/2008
2008 American Chemical Society

as a direct enantioselective acid-catalyzed activation of
nitroalkanes had not previously been described.
Table 1. Evaluation of Chiral Brønsted Acids in the Direct
Enantioselective Aza-Henry Reaction
Given that Brønsted acids are able to catalyze aldol
reactions we assumed that a chiral BINOL phosphate 1 could
play a bifunctional role in that it not only protonates the
aldimine but also accelerates the adjustment of the equilib-
rium between the nitroalkane and nitronate (eq 2)
(2)
yield time
entrya
aryl
(%)
(h)
drb
erc
Furthermore, in comparison to previously described meth-
ods, under these nonbasic conditions the corresponding
products should be configurationally stable. Hence, this new,
direct Brønsted-acid-catalyzed aza-Henry reaction would
enable, for the first time, simple yet efficient access to the
valuable ꢀ-nitro-R-amino acid esters. On the basis of our
earlier work regarding chiral ion pair catalysis, as well as
asymmetric Brønsted acid activation of imines7 and carbonyl
compounds,8 we started our experiments with the BINOL
phosphoric acid7–9 catalyzed nitro-Mannich reaction of
R-iminoester 2 and 1-nitropropane 3a (Table 1). It was shown
that the different substituted BINOL-phosphates 1a-f as well
as the corresponding octahydro derivatives 1g-i did indeed
catalyze the aza-Henry reaction and provided the amino acid
esters 4a in good diastereo- and enantiomeric ratios.
1
2
3
4
5
6
7
8
9
1a phenyl
4
15
44
19
13
65
72
62
20
168
6/1 56/44
1b 4-biphenyl
1c 1-naphthyl
1d 2-naphthyl
1e 3,5-(t-Bu)2-PMP
1f 9-phenanthryl
1g [H]8 Ph3Si
1h [H]8 9-phenanthryl
1i [H]8 4-phenoxyphenyl
168 10/1 80/20
144
168
168
120
18
6/1 41/59
8/1 53/47
5/1 91/9
6/1 82/18
9/1 82/18
8/1 85/15
8/1 47/53
120
120
a Reactions were performed at ambient temperature, using catalyst 1
(10 mol %) in 1-nitropropane (0.15 M). b Anti/syn ratio was determined
by 1H NMR. c The enantiomeric ratio of the anti diastereomer was
determined by HPLC analysis.
(6) Viso, A.; de la Pradilla, R. F.; Garcia, A.; Flores, A. Chem. ReV.
2005, 105, 3167.
Table 2. Influence of the Solvent on the
Brønsted-Acid-Catalyzed Direct Enantioselective Aza-Henry
Reaction
(7) (a) Rueping, M.; Azap, C.; Sugiono, E.; Theissmann, T. Synlett 2005,
2367. (b) Rueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.; Bolte, M.
Org. Lett. 2005, 7, 3781. (c) Rueping, M.; Theissmann, T.; Antonchick,
A. P. Synlett 2006, 1071. (d) Rueping, M.; Antonchick, A. P.; Theissmann,
T. Angew. Chem., Int. Ed. 2006, 45, 3683. (e) Rueping, M.; Antonchick,
A. P.; Theissmann, T. Angew. Chem., Int. Ed. 2006, 45, 6751. (f) Rueping,
M.; Sugiono, E.; Azap, C. Angew. Chem., Int. Ed. 2006, 45, 2617. (g)
Rueping, M.; Azap, C. Angew. Chem., Int. Ed. 2006, 45, 7832. (h) Rueping,
M.; Sugiono, E.; Theissmann, T.; Kuenkel, A.; Ko¨ckritz, A.; Pews Davtyan,
A.; Nemati, N.; Beller, M. Org. Lett. 2007, 9, 1065. (i) Rueping, M.;
Sugiono, E.; Schoepke, F. R. Synlett 2007, 1441. (j) Rueping, M.; Sugiono,
E.; Moreth, S. A. AdV. Synth. Catal. 2007, 349, 759. (k) Rueping, M.;
Antonchick, A.; P, Angew. Chem., Int. Ed. 2007, 46, 4562. (l) Rueping,
M.; Antonchick, A. P.; Brinkmann., C. Angew. Chem., Int. Ed. 2007, 46,
6903.
entrya
solvent
catalyst
yield (%)
drb
erc
1
2
3
4
5
6
7
8
toluene
toluene
toluene
benzene
CH2Cl2
CHCl3
1h
1f
10
12
42
45
35
12
47
33
5/1
5/1
75/25
89/11
95/5
95.5/4.5
88/12
80/20
91/9
1g
1g
1g
1g
1g
1g
12/1
13/1
12/1
13/1
11/1
8/1
(8) (a) Rueping, M.; Ieawsuwan, W.; Antonchick, A. P.; Nachtsheim,
B. J. Angew. Chem., Int. Ed. 2007, 46, 2097. (b) Rueping, M.; Nachtsheim,
B. J.; Moreth, S. M.; Bolte, M. Angew. Chem., Int. Ed. 2008, 47, 593.
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2006, 348, 999. (b) Akiyama, T. Chem. ReV. 2007, 107, 5744. (c) Appli-
cations: Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int.
Ed. 2004, 43, 1566. (d) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004,
126, 5356. (e) Hofmann, S.; Seayad, A. M.; List, B. Angew. Chem., Int.
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D. W. C. J. Am. Chem. Soc. 2006, 128, 84. (g) Terada, M; Sorimachi, K.;
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Chem., Int. Ed. 2006, 45, 4193. (j) Itoh, J.; Fuchibe, K.; Akiyama, T. Angew.
Chem., Int. Ed. 2006, 45, 4796. (k) Nakashima, D.; Yamamoto, H. J.
Am. Chem. Soc. 2006, 128, 9626. (l) Hoffmann, S.; Nicoletti, M.; List, B.
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(n-Bu)2O
AcOEt
91/9
a Reactions were performed at ambient temperature, using catalyst 1
(10 mol %), 10 equivalents of 1-nitropropane in solvent (0.05 M). b Anti/syn
ratio was determined by 1H NMR. c The enantiomeric ratio of the anti-
diastereomer was determined by HPLC analysis.
The best enantioselectivities were achieved with the
BINOL-phosphate 1e (Table 1, entry 5); however, the ste-
rically demanding triphenylsilyl-substituted Brønsted acid 1g
gave not only the best diastereoselectivity but also exhibited
increased reactivity compared to all the other catalysts tested
(Table 1, entry 7).
To further optimize the reaction, the imino ester protecting
group, the temperature, the catalyst loading, the concentra-
tion, and the solvent were varied. Thus, it was observed that
the reactivity, enantio-, and diastereoselectivity of the Brøn-
129, 12084
.
1732
Org. Lett., Vol. 10, No. 9, 2008

Table 3. Scope of the Enantioselective Brønsted-Acid-Catalyzed
Direct Enantioselective Aza-Henry Reaction
Scheme 1. Proposed Reaction Mechanism for the
Brønsted-Acid-Catalyzed Aza-Henry Reaction
ratio of 13/1. Under these optimized conditions we tested
different nitroalkanes in the BINOL-phosphate catalyzed,
enantio- and diastereoselective aza-Henry reaction (Table
3).10 In general, it was possible to successfully apply various
aliphatic and aromatic nitromethanes, whereby, the new
amino acid esters 4a-j were isolated for the first time in
good yields as well as very good diastereo- and enantiose-
lectivities.
With regard to the reaction mechanism we assume that
the chiral Brønsted acid 1 plays a bifunctional role (Scheme
1). On the one hand the R-iminoester 2 is activated by
the protonation of 1 which results in the formation of the
chiral ion pair A. On the other hand it can be assumed
that the adjustment of the nitroalkane/nitronate equilibrium
is also accelerated by 1. The addition of the nitronate 3a
to the activated imino ester A probably then occurs via
the intermediate B in which the chiral bifunctional
BINOL-phosphate acts simultaneously as a Brønsted acid
and as a Lewis base and which then results in the desired
amino acid ester 4.
a Reactions were performed at 30°C, using catalyst 1g (10 mol %), 10
equiv of nitroalkane in benzene (0.10 M) for 12-166 h. Isolated yield after
purification by column chromatography. b Anti/syn ratio was determined
by 1H-NMR. c The enantiomeric ratios of the anti diastereomers was
determined by HPLC analysis.
In summary we report here for the first time the develop-
ment of a new direct Brønsted acid catalyzed diastereo- and
enantioselective nitro-Mannich reaction of R-imino esters
with diverse nitroalkanes providing valuable ꢀ-nitro-R-amino
acid esters.11 Prior activation of the nitroalkane Via trans-
formation to silyl nitronates, as often previously reported, is
in our newly developed direct aza-Henry reaction no longer
necessary. Furthermore, the dual activation mode of the
BINOL-phosphate allows the reaction to be performed under
mild and strong base-free reaction conditions.
sted-acid-catalyzed aza-Henry reaction are profoundly de-
pendent on the solvent employed (Table 2).
In solvents such as THF, acetonitrile and dioxane almost
no transformation occurred. However, the reactions in
halogenated and aromatic solvents (Table 2, entry 1-6)
provided the enantiomerically enriched amino acid ester 4a.
The best enantio- and diastereoselectivities were achieved
in benzene and toluene and, thereby, the nitro-Mannich
reaction of iminoester 2 and nitroalkane 3a in the presence
of catalytic amounts 1g gave the desired amino acid ester
4a in an enantiomeric ratio of 96/4 er and in a diastereomeric
In addition, the reaction described here represents the
first example of the direct enantioselective Brønsted-acid-
catalyzed activation of nitroalkanes and allows the desired
Org. Lett., Vol. 10, No. 9, 2008
1733

amino acid esters to be isolated in good yields, excellent
enantioselectivities (up to 96/4 er) and with the widest
substrate scope to date. The concept of mild Brønsted-
acid-catalyzed activation of nitroalkanes as well as the
bifunctional activation through BINOL-phosphates is
promising with regard to the development of other
enantioselective transformations and is the focus of
ongoing research.
Acknowledgment. The authors acknowledge Evonik-
Degussa GmbH and the DFG (Schwerpunktprogramm Or-
ganokatalyse) for financial support.
Supporting Information Available: Experimental proce-
dures and spectral data for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL8003589
(11) The ꢀ-nitro-R-amino acid esters can be readily transferred into the
corresponding diamino acid, which has been demonstrated by Jørgense et
al., ref 4d.
(10) Detailed experimental information as well as the assignment of the
absolute configuration is provided in the Supporting Information.
1734
Org. Lett., Vol. 10, No. 9, 2008