Angewandte
Chemie
DOI: 10.1002/anie.201107877
Allylic Amination
Gold(I)-Catalyzed Enantioselective Intramolecular Dehydrative
Amination of Allylic Alcohols with Carbamates**
Paramita Mukherjee and Ross A. Widenhoefer*
Table 1: Effect of the nucleophile on the gold(I)-catalyzed intramolecular
amination of allylic alcohols (E)-1 under optimized conditions.[16,18]
The transition-metal-catalyzed enantioselective amination of
allylic esters and carbonates represents one of the most well-
established routes to chiral, nonracemic allylic amines.[1] With
the potential to condense synthetic sequences and reduce
waste streams, the dehydrative amination of allylic alcohols as
a route to enantiomerically enriched allylic amines has gained
considerable interest. However, while the stereospecific
amination of chiral secondary allylic alcohols has been
demonstrated,[2–4] the enantioselective amination of allylic
alcohols remains problematic.[5] Carreira et al. have reported
the IrI-catalyzed enantioselective amination of 1-cyclohexyl-
prop-2-enol with sulfamic acid in 70% ee.[6] Hartwig et al.
have reported the IrI/BPh3-catalyzed enantioselective inter-
molecular amination of primary allylic alcohols with aromatic
amines with up to 94% ee, but this method was restricted to
cinnamyl alcohols in the absence of a stoichiometric Lewis
acid promoter.[7] The groups of Yamamoto[8] and Kitamura[9]
have independently reported the enantioselective intramo-
lecular amination of allylic alcohols catalyzed by HgII and
RuII complexes, respectively. However, these methods were
restricted to sulfonamide nucleophiles and high enantiose-
lectivity was realized only for the formation of arene-fused
nitrogen heterocycles. Herein we report a gold-catalyzed
protocol for the intramolecular enantioselective amination of
allylic alcohols with carbamates to form five- and six-
membered aliphatic nitrogen heterocycles with up to 95% ee.
We recently reported the intramolecular dehydrative
amination of allylic alcohols with alkylamines catalyzed by
an achiral gold(I) phosphine complex.[4,10] Encouraged by the
high efficiency and stereospecificity of this transformation
and guided by both our previous work in the area of gold(I)-
catalyzed enantioselective allene hydroamination[11,12] and
Bandiniꢀs recent demonstration of gold(I)-catalyzed enantio-
selective arylation[13] and alkoxylation[14] of allylic alcohols,[15]
we targeted axially chiral bis(gold) complexes as catalysts for
the intramolecular enantioselective amination of the e-
benzylamino allylic alcohol (E)-1a (Table 1). Unfortunately,
optimization within this framework[16] proved largely unsuc-
cessful: treatment of (E)-1a with a catalytic 1:2 mixture of
[(S)-2](AuCl)2 and AgSbF6 in dioxane at 258C for 5 h led to
Entry
1+3, R[a]
X
Time [h]
Yield [%][b]
ee [%][c]
1
2
3
a, Bn
SbF6
ClO4
ClO4
ClO4
ClO4
ClO4
ClO4
5
100[d]
99
97
62
97
98
95
29
79
80
84
75
76
91
b, Cbz
c, Boc
d, Troc
e, CO2Me
f, Ts
48
48
48
48
48
48
4[e]
5
6
7
g, Fmoc
[a] Bn=benzyl, Cbz=benzyloxycarbonyl, Boc=tert-butyloxycarbonyl,
Troc=2,2,2-trichloroethoxycarbonyl, Ts=4-toluenesulfonyl, Fmoc=
fluorenylmethyloxycarbonyl. [b] Yield of isolated product. [c] Determined
by HPLC analysis on chiral support. [d] Conversion. [e] Reaction run at
408C.
quantitative conversion to 2-vinylpyrrolidine 3a, but with
only 29% ee (Table 1, entry 1).[17] We then focused our
attention on the manipulation of the nitrogen nucleophile as
a means to amplify stereoinduction (Table 1). These experi-
ments proved fruitful and gold(I)-catalyzed cyclization of
Fmoc-protected e-amino allylic alcohol (E)-1g employing an
optimized catalyst system comprised of [(S)-2](AuCl)2
(2.5 mol%) and AgClO4 (5 mol%) in dioxane at room
temperature for 48 h led to the isolation of (S)-3g in 95%
yield with 91% ee (Table 1, entry 7).[16,18]
The scope of this gold(I)-catalyzed enantioselective intra-
molecular amination was evaluated as a function of alkene
configuration, substitution, and ring size (Table 2). The
enantioselectivity of the amination was sensitive to the
alkene configuration: (Z)-1g was converted into 3g in 99%
yield with ꢀ 5% ee (Table 2, entry 1). Although e-amino
allylic alcohols that possessed gem-dialkyl substitution at the
homoallylic position cyclized with higher enantioselectivity
than did an unsubstituted e-amino allylic alcohol (Table 2,
entries 2–4), homoallylic gem-disubstitution was not required
for high enantioselectivity (Table 2, entries 5 and 6). For
example, gold(I)-catalyzed cyclization of 4, which possessed a
single phenyl group at the homoallylic position, led to
isolation of pyrrolidine 5 in 87% yield as a 1:1 mixture of
[*] P. Mukherjee, Prof. R. A. Widenhoefer
French Family Science Center, Duke University
Durham, NC 27708–0346 (USA)
E-mail: rwidenho@chem.duke.edu
[**] We thank the NIH (GM-080422) for support of this research. P.M.
thanks Duke University for support provided through the Burroughs
Welcome and C.R. Hauser Fellowships.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2012, 51, 1405 –1407
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1405