Gold(I)-catalyzed intramolecular hydroamination of unactivated C=C bonds with alkyl ammonium salts

Article abstract of DOI:10.1039/b804081h

A mixture of (5)AuCl {5 = PCy₂[2-(2,6-C₆H ₃(OMe)₂)C₆H₄]} and AgOTf catalyzes the intramolecular hydroamination of unactivated C=C bonds with primary and secondary ammonium salts. The Royal

Full text of DOI:10.1039/b804081h

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COMMUNICATION
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Gold(I)-catalyzed intramolecular hydroamination of unactivated CQC
bonds with alkyl ammonium saltsw
Christopher F. Bender and Ross A. Widenhoefer*
Received (in College Park, MD, USA) 10th March 2008, Accepted 4th April 2008
First published as an Advance Article on the web 19th May 2008
DOI: 10.1039/b804081h
A mixture of (5)AuCl {5 = PCy2[2-(2,6-C6H3(OMe)2)C6H4]}
and AgOTf catalyzes the intramolecular hydroamination of
unactivated CQC bonds with primary and secondary ammo-
nium salts.
catalyzed protocol for the intramolecular hydroamination of
unactivated CQC bonds with primary and secondary alkyl
ammonium salts.
We targeted the gold N-heterocyclic carbene complex
(1)AuCl [1
=
1,3-bis(2,6-diisopropylphenyl)imidazol-2-
ylidine] and the o-biphenylphosphine complex (2)AuCl
[2 = P(t-Bu)2o-biphenyl] as precatalysts for the intramolecular
hydroamination of alkenes with alkylammonium salts owing
to their effectiveness as precatalysts for the hydroamination of
N-alkenyl carboxamide derivatives.10,12 Initial experiments
were disappointing, and reaction of benzyl 4-pentenyl ammo-
nium salt 3ꢀHBF4 with a catalytic mixture of either (1)AuCl or
(2)AuCl and AgOTf (5 mol%) in dioxane at 60 1C for 22 h
followed by basification formed pyrrolidine 4 in 3% and 11%
yield, respectively (Table 1, entries 1 and 2). However, sub-
sequent optimization of the conversion of 3ꢀHBF4 to 4 cata-
lyzed by (2)AuCl/AgOTf identified toluene as a markedly
superior solvent for hydroamination (Table 1, entry 6). Opti-
mization of the gold(I)-catalyzed conversion of 3ꢀHBF4 to 4 in
The transition metal-catalyzed addition of the N–H bond of
an amine or carboxamide derivative across a C–C multiple
bond (hydroamination) has attracted considerable attention as
an atom economical and potentially expedient route to nitro-
gen heterocycles.1 The hydroamination of unactivated CQC
bonds with alkylamines represents one of the most challenging
permutations of this transformation. Although complexes of
rare earth,2 alkali,3 alkaline earth,4 and group 45 metals
catalyze the intramolecular hydroamination of unactivated
CQC bonds with alkyl amines, the synthetic utility of these
procedures is compromised by the excessive oxophilicity and/
or basicity of the catalysts. Conversely, the hydroamination of
unactivated CQC bonds with alkylamines catalyzed by late
transition metal complexes, which holds promise owing to
the low oxophilicity of these complexes, has been realized
in only two cases. We have shown that mixtures of
[PtCl2(H2CQCH2)]2 and PPh3 catalyze the intramolecular
hydroamination of alkenes with secondary alkylamines,6 while
Liu and Hartwig have recently reported that mixtures of
[Rh(COD)2]BF4 and PCy2[2-(2-C6H4NMe2)C6H4] catalyze
the hydroamination of alkenes with both primary and second-
Table 1 Ligand and solvent dependence of the gold(I)-catalyzed
hydroamination of 3ꢀHBF4
ary alkylamines.7–9
z
Concurrent with the recent proliferation of gold(I)-catalyzed
organic transformations10,11 has been the development of a
number of gold(I)-catalyzed protocols for the hydroamination
of unactivated CQC bonds with carboxamide derivatives12
and sulfonamides.13 However, extension of gold(I)-catalyzed
alkene hydroamination to include alkylamines has not been
demonstrated, presumably due to non-productive displace-
ment of the alkene by the amine and/or inefficient protonolysis
of Au–C bonds with the weakly acidic ammonium salt (pKa =
10–11). Inspired by the efforts of Venanzi8 and Trogler,14 we
considered that employment of alkylamines in their proto-
nated form might ameliorate both of these problems, provided
that a sufficient concentration of free amine would be available
for nucleophilic attack. Indeed, here we report a gold(I)-
Entry
1
Ligand
Solvent
Yielda (%)
Ar = 2,5-C6H3(i-Pr)2 (1)
Dioxane
3
2
3
4
5
6
7
8
9
R1 = t-Bu, R2 = R3 = H (2)
Dioxane
MeOH
THF
EtOAc
Toluene
Toluene
11
48
15
37
61
27
77
99
2
2
2
2
R1 = Cy, R2 = R3 = H
French Family Science Center, Duke University, Durham, North
Carolina, USA. E-mail: rwidenho@chem.duke.edu;
Fax: +1-919-6601605; Tel: +1-919-6601533
w Electronic supplementary information (ESI) available: Experimental
procedures, spectroscopic data, and scans of NMR spectra. See DOI:
10.1039/b804081h
R1 = t-Bu, R2 = NMe2, R3 = H Toluene
R1 = Cy, R2 = R3 = OMe (5)
Toluene
a
Determined by GC analysis of the crude reaction mixture after
treatment with NaOH.
ꢁc
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Table 2 Intramolecular hydroamination of alkenes with alkylammo-
nium salts catalyzed by a 1 : 1 mixture of (5)AuCl and AgOTf (5
mol%) in toluene at 80 1C for 18–24 h
Entry Alkene
1
Heterocycle
Yielda (%)
82
3ꢀHBF4
4
Scheme 1
in 93% yield (Table 2, entry 3). Conversely, the efficiency of
hydroamination was sensitive to the nature of the ammonium
counterion and gold(I)-catalyzed hydroamination of 6ꢀHOTf
formed 7 in only 43% yield (Table 2, entry 4). The dienyl
ammonium salt 8ꢀHBF4 underwent intramolecular hydroami-
nation to form pyrrolidine 9 in good yield with modest
diastereoselectivity (Table 2, entry 5). Gold(I)-catalyzed hy-
droamination of 5-hexenyl ammonium salt 10ꢀHBF4 led to
isolation of piperidine 11 in 91% yield (Table 2, entry 6).
Secondary and aromatic piperidine derivatives were also
accessible via gold(I)-catalyzed hydroamination, albeit with
significantly diminished efficiency (Table 2, entries 7 and 8).
Internal alkenes failed to undergo hydroamination under these
conditions.
2
X = BF4 (6ꢀHBF4)
X = BF4 (6ꢀHBF4)
X = OTf (6ꢀOTf)
7
94
93
3b
4
43c
5d
93 (1.9 : 1)
8ꢀHBF4 (Ar = 4-MeOC6H4)
9
Stereochemical analysis of gold(I)-catalyzed hydrofunctio-
nalization has consistently supported outer-sphere mechan-
isms for C–X bond formation.13,15 As such, we envision a
mechanism for the gold(I)-catalyzed hydroamination of alkyl
alkenyl ammonium salts initiated by formation of a gold p-
alkene complex I (Scheme 1). Deprotonation of the pendant
ammonium salt followed by outer-sphere attack of the free
amine on the complexed alkene of II would form the cationic
pyrrolidine complex III. Protonolysis of the Au–C bond of III
6
7
R = H (10ꢀHBF4)
R = Bn (12ꢀHBF4)
11
13
91
21c
8d
45c
+
with HNR3 would then release the protonated pyrrolidine.
Acknowledgment is made to the NSF (CHE-0555425), NIH
(GM-080422), and Johnson&Johnson for support of this
research.
a
Material of Z 95% purity isolated after basification of the reaction
mixture with NaOH. Ammonium salt generated in situ from free
b
c
amine and HBF4ꢀOEt2 (1 : 1) prior to catalyst introduction. Yield
d
determined by GC analysis of the basified reaction mixture. Reac-
tion run with 10% catalyst loading at 100 1C.
Notes and references
z Venanzi and co-workers reported the Pt-catalyzed intramolecular
hydroamination of alkenyl amines under acidic conditions, but these
transformations were prohibitively slow.8 More recently, Ackermann
et al. have demonstrated the intramolecular hydroamination of alkyl
4-pentenyl amines under Brønsted acid catalysis at 120–130 1C.9
y Heating a solution of 3ꢀHBF4 or a mixture of 3ꢀHBF4 and either 5,
AgOTf, or (5)AuCl (15 mol%) in toluene at 80 1C for 17 h followed by
basification with NaOH led to no detectable formation of 4.
toluene as a function of phosphine identified PCy2{2-[2,6-
C6H3(OMe)2]C6H4} (5) as a highly effective supporting ligand
(Table 1, entry 9). In a preparative scale reaction, treatment of
3ꢀHBF4 with a catalytic 1 : 1 mixture of (5)AuCl and AgOTf in
toluene at 80 1C for 17 h followed by treatment with NaOH
led to isolation of 4 in 82% yield (Table 2, entry 1).y
Primary alkyl 4-pentenyl ammonium salts underwent intra-
molecular hydroamination more efficiently than did secondary
alkyl salts. As an example, reaction of 6ꢀHBF4 with (5)AuCl/
AgOTf led to isolation of pyrrolidine 7 in 94% yield (Table 2,
entry 2). Employment of preformed ammonium salt was not
required for efficient hydroamination and sequential treatment
of 6 with HBF4ꢀOEt2 and (5)AuCl/AgOTf led to isolation of 7
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