Enantioselective rhodium-catalyzed synthesis of branched allylic amines by intermolecular hydroamination of terminal allenes

Article abstract of DOI:10.1002/anie.201206594

Branching out: The rhodium-catalyzed enantioselective hydroamination of monosubstituted allenes with anilines permits the atom-economic synthesis of valuable branched allylic amines. In contrast to previous linear selective allene hydroaminations, a Rh

Full text of DOI:10.1002/anie.201206594

Angewandte
Chemie
DOI: 10.1002/anie.201206594
Asymmetric Catalysis
Enantioselective Rhodium-Catalyzed Synthesis of Branched Allylic
Amines by Intermolecular Hydroamination of Terminal Allenes**
Michael L. Cooke, Kun Xu, and Bernhard Breit*
a-Chiral allylic amines are an important, versatile class of
building blocks for organic synthesis that can be employed in
the formation of a diverse array of nitrogen-containing
molecules, and many strategies for their enantioselective
synthesis have been developed.[1] Several of the most general
methods (for example, allylic substitution, the Overman
rearrangement, or imine vinylation) require either activated
substrates and/or stoichiometric amounts of either a leaving
group or an organometallic reagent, which makes them less
attractive in terms of atom and/or step economy.[2,3] Catalytic
enantioselective intermolecular hydroamination is a highly
attractive, atom economical approach for the synthesis of
non-racemic amines and their derivatives, and has been the
subject of much attention.[4] Despite extensive effort, efficient
methods for catalytic enantioselective intermolecular hydro-
amination are rare.[5] Although the enantioselective inter-
Scheme 1. Intermolecular hydroamination of allenes. For the structure
molecular hydroamination of allenes would be an efficient
of Josiphos, see Table 1. cod=1,5-cyclooctadiene, L=ligand.
method for the synthesis of a-chiral allylic amines,[6,7] only
one example has been reported, which requires internal
allenes, has a limited scope, and provides only moderate levels
of enantioselectivity (Scheme 1a).[8,9] To date, the enantio-
selective intermolecular hydroamination of mono-substituted
allenes has not been reported, owing to the propensity of
many hydroamination catalysts to form achiral products
(either imines or linear allylic amines) from such substrates
(Scheme 1b).[10] Herein, we report the first example of the
enantioselective intermolecular hydroamination of mono-
substituted allenes, producing versatile branched allylic
amines with perfect regioselectivity, high yield and good
enantioselectivity (Scheme 1c).
During the course of our investigations into the atom-
economic functionalization of terminal alkynes and allenes,[11]
we identified a rhodium-catalyzed method to access valuable,
enantioenriched branched allylic esters from terminal allenes
and carboxylic acids.[11b] We hypothesized that an appropriate
nitrogen nucleophile could permit the synthesis of branched
allylic amines in an analogous manner.[12]
Our preliminary studies in this area focused on the
identification of an appropriate nitrogen nucleophile. After
testing a range of nucleophiles and conditions (see the
Supporting Information for details), we were pleased to
identify that a mixture of [{Rh(cod)Cl}2] (cod = 1,5-cyclo-
octadiene) and DPEphos (3; see Table 1 for structure) in
a mixture of 1,2-dichloroethane (DCE) and ethanol (1:2)
effectively catalyzed the hydroamination of cyclohexylallene
with aniline, affording the desired branched allylic amine 2a
exclusively in 69% yield (Table 1, entry 1). With an effective
method for the racemic intermolecular hydroamination in
hand, we then tested a range of chiral bidentate phosphine
ligands in the reaction (entries 2–12). Whereas most of the
ligands tested resulted in poor yield and/or enantioselectivity
(entries 2–4), Josiphos ligand 7a afforded 2a in a promising
33% yield and 66% ee (entry 5). Other Josiphos ligands were
tested and, pleasingly, 7c afforded 2a in 83% yield with 78%
ee (entry 7). We were able to reduce the catalyst loading to
1 mol% in combination with 3 mol% of the ligand without
significant detriment to either the yield or enantioselectivity
of the reaction (entry 8). Further screening revealed that a 9:1
ratio of DCE:EtOH is optimal (entry 9). In contrast to the
reaction using ligand 3, the reaction does proceed in the
absence of EtOH with 7c, although with reduced yield and
enantioselectivity. We determined that the ratio of allene to
aniline can be reduced to 1.2:1 (entry 11), with no detrimental
effects. Although the reaction still proceeds with only
0.1 mol% of the catalyst precursor, the yield and enantio-
meric excess are somewhat reduced (entry 12). A single
recrystallization of the HCl salt allows 2a to be obtained in
[*] Dr. M. L. Cooke, K. Xu, Prof. Dr. B. Breit
Institut fꢀr Organische Chemie und Biochemie, Freiburg Institute
for Advanced Studies (FRIAS), Albert-Ludwigs-Universitꢁt Freiburg
Albertstrasse 21, 79104 Freiburg im Breisgau (Germany)
E-mail: bernhard.breit@chemie.uni-freiburg.de
[**] This work was supported by the DFG, the International Research
Training Group “Catalysts and Catalytic Reactions for Organic
Synthesis” (IRTG 1038), the Fonds der Chemischen Industrie, and
the Krupp Foundation. We thank Umicore, BASF, and Wacker for
generous gifts of chemicals.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206594.
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Table 1: Optimization of enantioselective hydroamination.
Entry
Ligand
DCE/EtOH
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
3
4
5
6
7a
7b
7c
7c
7c
7c
7c
7c
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
9:1
1:0
9:1
9:1
69
26
11
55
33
0
83
85
95
63
94
50
–
54
33
32
66
–
78
74
8[c]
9[c]
10
11[c,d]
12[d,e]
89
84
89
80(98)[f]
[a] Yield of isolated product. [b] Determined by HPLC analysis on a chiral
stationary phase. [c] Using [{Rh(cod)Cl}2] (1 mol%) and ligand
(3 mol%). [d] Allene/amine ratio was 1.2:1. [e] Using [{Rh(cod)Cl}2]
(0.1 mol%) and ligand (0.3 mol%). [f] Value in parentheses is the ee
obtained after a single recrystallization of the HCl salt.
98% ee, which demonstrates the utility of this method for the
synthesis of enantiopure allylic amines.
Following the establishment of optimized conditions, we
investigated the scope of anilines in the enantioselective
intermolecular hydroamination reaction (Scheme 2). A wide
range of substituted anilines were suitable substrates for the
reaction, with good to excellent yields and good enantiomeric
excesses observed in most cases. Alkyl substituents were well
tolerated in all positions (2b–d). A range of halide-substituted
anilines could be coupled, providing allylic amines suitable
for a range of cross-coupling reactions (2e–j). A variety of
other para-substituted anilines were also compatible, includ-
ing p-anisidine, the product of which (2k) can be readily
deprotected to afford the free allylic amine.[13] Unprotected
alcohols and phenols are also compatible with this method
(2m,n), although slightly reduced enantioselectivity was
observed for phenol 2m. Other aromatic amines were also
suitable substrates for the reaction, with 5-aminoindole and
1-naphthylamine affording the corresponding allylic amines
2o and 2p in good yields and enantiomeric excesses. Electron-
deficient anilines are more challenging substrates and require
slightly elevated temperatures (1008C vs. 808C); however,
products bearing esters, ketones, and trifluoromethyl groups
(2q–s) can be obtained in moderate yields with slightly
reduced enantiomeric excesses.
Scheme 2. Scope of anilines in the enantioselective rhodium-catalyzed
hydroamination. [a] Reaction carried out at 708C. [b] Reaction carried
out at 1008C.
We then investigated the scope of the allene coupling
partner (Scheme 3). The terminal allenes used were readily
prepared in one or two steps from commercially available
starting materials (see the Supporting Information for
details). As well as a-branched allenes, linear alkyl-substi-
tuted allenes were suitable substrates (8 and 9). Protected
alcohols were also tolerated in the reaction (10 and 11),
although slightly lower enantiomeric excess was observed
with TBS protected alcohol (10). A phthalimide bearing
allene was also compatible, affording differentially protected
diamine 12 in excellent yield and good enantiomeric excess.
Isotopic labeling experiments were carried out with
[D7]aniline (Scheme 4).[14] In accordance with our observa-
tions on the addition of carboxylic acids to allenes,[11b]
deuterium incorporation was observed at all positions of the
alkene.
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accordance with that observed previously for other
p-allylrhodium complexes.[16]
In summary, we have developed the first method for the
enantioselective intermolecular hydroamination of terminal
allenes with anilines. A broad range of valuable branched
allylic amines can be isolated in excellent yields and good
enantioselectivities in an atom-economic manner using a cat-
alyst derived from a commercially available rhodium source
and a Josiphos ligand. Further studies will focus on mecha-
nistic investigations and the extension of this method to other
nucleophiles.
Received: August 15, 2012
Published online: && &&, &&&&
Keywords: allylic compounds · asymmetric catalysis ·
.
asymmetric synthesis · hydroamination · rhodium
Scheme 3. Scope of allenes in the enantioselective rhodium-catalyzed
hydroamination. [a] Absolute configuration determined by comparison
with known compound. TBS=tert-butyldimethylsilyl, Trt=triphenyl-
methyl.
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Scheme 5. Proposed mechanism for the rhodium-catalyzed allene
hydroamination.
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Asymmetric Catalysis
M. L. Cooke, K. Xu,
B. Breit*
&&&& — &&&&
Enantioselective Rhodium-Catalyzed
Synthesis of Branched Allylic Amines by
Intermolecular Hydroamination of
Terminal Allenes
Branching out: The rhodium-catalyzed
enantioselective hydroamination of mon-
osubstituted allenes with anilines permits
the atom-economic synthesis of valuable
branched allylic amines. In contrast to
previous linear selective allene hydro-
aminations, a RhI/Josiphos catalyst
system (see scheme) allows branched
allylic amines to be obtained with perfect
regioselectivity, high yield, and good
enantioselectivity.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
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www.angewandte.org
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