Catalytic asymmetric aminoallylation of aldehydes: A catalytic enantioselective aza-cope rearrangement

Article abstract of DOI:10.1002/anie.200803610

(Chemical Equation Presented) A condensation-rearrangement sequence forms the basis of a high-yielding route to chiral homoallylic amines from readily accessible aldehydes (see scheme). This transformation is both the first enantioselective Bronsted acid catalyzed sigmatropic rearrangement and the first example of a catalytic asymmetric aza-Cope rearrangement.

Full text of DOI:10.1002/anie.200803610

Communications
DOI: 10.1002/anie.200803610
Asymmetric Synthesis
Catalytic Asymmetric Aminoallylation of Aldehydes: A Catalytic
Enantioselective Aza-Cope Rearrangement**
Magnus Rueping* and Andrey P. Antonchick
Efficient catalytic enantioselective variants of many signifi-
cant organic reactions have been developed, including
biocatalytic and metal-catalyzed processes, but increasingly
also organocatalytic methods. Sigmatropic rearrangements
are among the fundamental methods for the preparation of
complex organic molecules and have found widespread
application in the synthesis of biologically relevant molecules
and natural products. A variety of catalytic asymmetric
sigmatropic rearrangements have already been reported.[1]
Most are based on the use of chiral metal complexes;
however, individual organocatalytic enantioselective variants
have also been described in which chiral secondary amines,[2]
cinchona alkaloids,[3] and guanidium salts[4] serve as the
catalysts. Surprisingly, no successful catalytic enantioselective
aza-Cope rearrangement has been reported to date,[5] despite
the importance of the corresponding products in synthetic
organic chemistry. Given the relevance of sigmatropic rear-
rangements and the resulting products, as well as the limited
success in the development of an asymmetric version, we
viewed the development of an asymmetric aminoallylation of
aldehydes[6] on the basis of a catalytic enantioselective 2-aza-
or 2-azonia-Cope rearrangement as an important goal
[Eq. (1)]. Such a transformation would provide an efficient
route to optically active homoallylic amines, which are
particularly useful building blocks for the synthesis of natural
products[7] and valuable precursors of other organic com-
pounds, including b-amino acids, aminoalcohols, aminoep-
oxides, pyrrolidines, and piperidines.[8,9] Herein, we report the
development of a catalytic asymmetric aminoallylation of
aldehydes on the basis of a condensation–rearrangement
sequence.
phosphoric acid diester 1 would result initially in the
formation of an iminium ion in the form of a chiral ion pair
A. We further anticipated that activation by the Brønsted acid
would be strong enough to accelerate the following aza-Cope
rearrangement to the adduct B. Subsequent reprotonation
should then provide the desired optically active homoallylic
amine 4 with regeneration of the chiral Brønsted acid 1.
In continuation of our studies on the organocatalyzed
activation of imines[10] and carbonyl compounds,[11] and on the
basis of our experience in asymmetric ion-pair and hydrogen-
bond catalysis, we decided to examine a phosphoric acid
catalyzed 2-aza-Cope rearrangement (Scheme 1). In planning
our reaction, we assumed that the aminoallylation of an
aldehyde 2 with an amine 3 under the catalysis of a
Scheme 1. Brønsted acid catalyzed aza-Cope rearrangement.
Our initial experiments revealed that Brønsted acid
catalyzed Cope rearrangements can be performed with 1,1-
diaryl homoallylic amines 3 in combination with aldehydes 2
and a catalytic amount of diphenyl phosphoric acid diester.
Hence, in our attempt to develop an asymmetric variant of the
transformation we investigated the application of various
chiral phosphoric acid diesters 1a–o as catalysts
(Table 1).[12–14] We observed the best results with regard to
the enantiomeric ratio of the product with (R)-3,3’-bis-
(naphthyl)octahydrobinol (1h) as the catalyst (Table 1,
entry 8). To further optimize the reaction conditions, we
varied the solvent, the concentration of the reaction mixture,
the reaction temperature, and the catalyst loading and found
that the Brønsted acid catalyzed enantioselective Cope
rearrangement can be performed in various aprotic solvents.
[*] Prof. Dr. M. Rueping, Dr. A. P. Antonchick
Degussa Endowed Professorship
Institute of Organic Chemistry und Chemical Biology
Goethe University Frankfurt am Main
Max-von-Laue Strasse 7, 60438 Frankfurt am Main (Germany)
Fax: (+49)69-798-29248
E-mail: m.rueping@chemie.uni-frankfurt.de
[**] We acknowledge Evonik Degussa and the DFG (Priority Program
Organocatalysis) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200803610.
10090
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Table 1: Evaluation of chiral Brønsted acid catalysts in the enantiose-
Table 2: Reaction parameters of the Brønsted acid catalyzed enantiose-
lective sigmatropic rearrangement.[a]
lective 2-aza-Cope rearrangement.[a]
Entry
Solvent
1h [mol%]
e.r.[b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15[c]
toluene
toluene
toluene
toluene
benzene
o-xylene
p-xylene
mesitylene
cyclohexane
cumene
ethylbenzene
PhCF3
10
15
5
87.5:12.5
86.5:13.5
82.5:17.5
59.5:40.5
78.5:21.5
86:14
85.5:14.5
85.5:14.5
78:22
85.5:14.5
85.5:14.5
82.5:17.5
55.5:44.5
86:14
Entry
1
R
e.r.[b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a
1b
1c
1d
1e
1 f
1g
2-naphthyl
4-biphenyl
75:25
3
72.5:27.5
51.5:48.5
51.5:48.5
racemate
51.5:48.5
racemate
87.5:12.5
72:28
racemate
52:48
51.5:48.5
51.5:48.5
59.5:40.5
64.5:35.5
10
10
10
10
10
10
10
10
10
10
10
9-anthracenyl
9-phenanthryl
3,5-(CF3)2-Phenyl
4-nitrophenyl
3,5-tBu2-4-MeOC6H2
2-naphthyl
4-biphenyl
Ph3Si
9-phenanthryl
3,5-(CF3)2C6H3
3,4,5-F3C6H2
4-FC6H4
1h [H8][c]
1i [H8][c]
1j [H8][c]
1k [H8][c]
1l [H8][c]
1m [H8][c]
1n [H8][c]
1o [H8][c]
1,4-dioxane
nBu2O
MTBE
91:9
[a] Reaction conditions: 3a, 2a (1.1 equiv), 1h (3–15 mol%), 3-ꢀ MS,
608C. [b] The enantiomeric ratio was determined by HPLC on a chiral
phase (chiralcel OD-H). [c] The reaction was carried out at 508C.
4-MeOC6H4
[a] Reaction conditions: 3a, 2a (1.5 equiv), 1 (10 mol%), 3-ꢀ molecular
sieves (MS), toluene, 608C. [b] The enantiomeric ratio was determined
by HPLC on a chiral phase (chiralcel OD-H). [c] The octahydrobinol
catalyst was used.
The highest reactivity and selectivity were observed when the
reaction was carried out in methyl tert-butyl ether (MTBE) at
508C (Table 2).
We examined the scope of the Brønsted acid catalyzed
enantioselective [3,3] sigmatropic rearrangement under the
optimized reaction conditions with respect to the aldehyde
substrate (Table 3). Diverse aldehydes with electron-with-
drawing and electron-donating substituents underwent the
desired transformation to give homoallylic amines 4a–k in
good yields with very good enantioselectivities.[15]
The products 4 of our catalytic enantioselective amino-
allylation of aldehydes are important synthetic intermediates,
which can, for example, be transformed readily into the free
homoallylic amines or N-benzhydryl-protected primary
amines. To demonstrate the synthesis of such compounds
and determine the absolute configuration, we first subjected
aldehyde 2h to catalytic asymmetric transfer aminoallylation
(Scheme 2). The optically active product 4h was transformed
into the protected amine 5h in good yield by treatment with
sodium cyanoborohydride. Alternatively, the free primary
optically active homoallylic amine 6h was obtained by the
treatment of 4h with hydroxyamine hydrochloride.[16]
In summary, we have described the development of a
Brønsted acid catalyzed asymmetric aminoallylation of alde-
hydes. The condensation–rearrangement described is not only
based on the first enantioselective Brønsted acid catalyzed
sigmatropic rearrangement but is also the first example of a
Scheme 2. Catalytic enantioselective transfer aminoallylation and trans-
formation of the product into a chiral primary amine and an
N-benzhydryl-protected homoallylic amine.
catalytic asymmetric aza-Cope rearrangement. This trans-
formation of readily available aldehydes provides efficient
access to synthetically useful primary homoallylic amines in
good yields and with very good enantioselectivities (e.r. up to
97:3). We expect this asymmetric organocatalytic aza-Cope
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Communications
Table 3: (Continued)
Table 3: Scope of the Brønsted acid catalyzed enantioselective amino-
allylation of aldehydes.[a]
Entry
Product
Yield [%][b]
e.r. [%][c]
97:3
10
75
Entry
1
Product
Yield [%][b]
e.r. [%][c]
91:9
77
11
80
90.5:9.5
[a] Reaction conditions: 3a, aldehyde (1.1 equiv), 1h (10 mol%), 3-ꢀ
MS, MTBE, 508C, 48 h. [b] Yield of the isolated product after column
chromatography. [c] The enantiomeric ratio was determined by HPLC on
a chiral phase.
2
3
4
67
87
61
92.5:7.5
90.5:9.5
93.5:6.5
rearrangement to be very useful for the synthesis of diverse
biological compounds and natural products. Our current
research is focused of the development of further asymmetric
organocatalytic sigmatropic rearrangements with Brønsted
acid catalysts.
Received: July 24, 2008
Published online: November 21, 2008
Keywords: allylation · Brønsted acids · ion pairs ·
.
organocatalysis · sigmatropic rearrangement
5
6
74
52
94:6
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