Gold(I)-catalyzed intramolecular hydroamination of alkenyl carbamates

Article abstract of DOI:10.1002/anie.200600052

(Chemical Equation Presented) Gold for rings: Reaction of alkenyl carbamates such as 1 in the presence of [Au{P(tBu)₂(o-biphenyl)}]Cl and AgOTf led to nitrogen heterocycles (e.g. 2). This Au^I-catalyzed intramolecular hydroamination t

Full text of DOI:10.1002/anie.200600052

Angewandte
Chemie
Although platinum-catalyzed intramolecular hydroami-
nation displayed good functional-group compatibility, the
procedure required reaction temperatures of 1208C and
displayed a limited substrate scope.[2] Preliminary mechanistic
experiments pointed to protonolysis of heterobicyclic amine
complex 3 with an amine hydrochloride as the turnover-
limiting step in the Pt-catalyzed conversion of 1 into 2
[Eq. (2)].[2] On the basis of this insight, we reasoned that
employment of a less basic amine derivative might lead to a
more efficient and more general hydroamination protocol.
Indeed, herein we report a mild and effective Au-catalyzed
protocol for the intramolecular hydroamination of alkenyl
carbamates to form protected nitrogen heterocycles.
Hydroamination (2)
Although tosylamides have been employed to good effect
[3]
À
DOI: 10.1002/anie.200600052
in the catalytic amination of C C multiple bonds, the
strongly reducing conditions required for subsequent depro-
tection compromises the utility of these transformations.[4,5]
For this reason, we targeted benzyl carbamates, which
undergo deprotection under mild conditions,[4] as nucleo-
philes for the catalytic intramolecular hydroamination of
unactivated olefins. Selective hydroamination of alkenyl
carbamates has previously been achieved only through
employment of a stoichiometric amount of HgII followed by
reduction.[6,7] Unfortunately, attempted hydroamination of
carbamate 4 employing the catalyst system optimized for the
hydroamination of 1 required 1208C and formed protected
pyrrolidine 5 in only 50% yield (determined by 1H NMR
spectroscopic analysis) [Eq. (1)].[8]
Gold(i)-Catalyzed Intramolecular
Hydroamination of Alkenyl Carbamates**
Xiaoqing Han and Ross A. Widenhoefer*
Intramolecular hydroamination of unactivated olefins has
received considerable attention as an attractive and poten-
tially expedient route to the synthesis of functionalized
nitrogen heterocycles.[1] However, despite this prolonged
focus, a general and efficient procedure has not been
realized.[1] In response to this limitation, we recently reported
a platinum-catalyzed procedure for the intramolecular hydro-
amination of unactivated olefins with secondary alkyl
amines.[2] As an example, reaction of N-benzyl-4-pentenyl-
A number of recent reports have documented the utility
of cationic AuI–phosphine complexes as catalysts for the
addition of carbon[9,10] and oxygen[11–13] nucleophiles to
alkenes and alkynes.[14,15] For this reason, we considered that
cationic AuI–phosphine complexes might also catalyze the
addition of nitrogen nucleophiles to unactivated olefins. An
initial experiment was encouraging and treatment of 4 with a
catalytic 1:1 mixture of [Au(PPh3)Cl] and AgOTf in toluene
at 1008C for 24 h led to 5 in 59% yield (1H NMR; Table 1,
entry 1). Subsequent experimentation led to identification of
a significantly more active catalyst system for the conversion
of 4 into 5 that employed a catalytic 1:1 mixture of [Au{P-
(tBu)2(o-biphenyl)}]Cl (6) and AgOTf in dioxane at 1008C
(Table 1, entries 2–8).[16] This catalyst system was also effec-
tive at lower temperatures and, in a preparative-scale
reaction, treatment of 4 with a catalytic 1:1 mixture of 6 and
AgOTf (5 mol%) in dioxane at 608C for 18 h led to 5 in 97%
yield (Table 2, entry 1). Comparison of P(tBu)2(o-biphenyl)
and PMe2Ph as ligands for the AuI-catalyzed hydroamination
of 4 suggests that steric rather than electronic factors are
responsible for the high efficiency of the former ligand
(Table 1, entries 7 and 8).
=
amine (1) with a catalytic 1:2 mixture of [{PtCl2(H2C CH2)}2]
and PPh3 at 1208C for 16 h led to isolation of pyrrolidine 2 in
75% yield (88% by GC) [Eq. (1)].
[*] X. Han, Prof. R. A. Widenhoefer
P. M. Gross Chemical Laboratory
Duke University
Durham, NC 27708-0346 (USA)
Fax: (+1)919-660-1605
E-mail: rwidenho@chem.duke.edu
[**] We thank the PRF (43636-AC1), administered by the American
Chemical Society, the Camille and Henry Dreyfus Foundation, and
GlaxoSmithKline for support of this research.
Neither the rate nor the yield of the AuI-catalyzed
conversion of 4 into 5 was affected by the presence of water
(1 equiv) (Table 2, entry 2). Gold-catalyzed intramolecular
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Effect of phosphine and solvent on the AuI-catalyzed hydro-
amination of 4.
Table 2: Hydroamination of alkenyl carbamates catalyzed by a 1:1 mixture of
Au[P(tBu)2(o-biphenyl)]Cl (6) and AgOTf (5 mol%) in dioxane.
Entry
Alkene
Heterocycle
Temp [8C] Time [h] Yield [%][a]
Entry
PR3
Solvent
Yield [%][a]
1
2
3
4
5
6
7
8
PPh3
PPh3
PPh3
PPh3
P(4-C6H4OMe)3
P(4-C6H4CF3)3
PMe2Ph
toluene
CH3CN
C2H4Cl2
dioxane
dioxane
dioxane
dioxane
dioxane
59
49
33
75
70
23
7
1
2
3
4
5
R=Cbz
R=Cbz
R=Boc
R=Moz
R=Fmoc
60
60
60
60
60
18
18
20
16
24
97
96[b]
96
95
93
P(tBu)2(o-biphenyl)
98
[a] Yield determined by 1H NMR spectroscopic analysis of the crude
reaction mixture. Tf=trifluoromethanesulfonyl.
6
7
R=H
R=Me
60
80
23
40
96
88
hydroamination was compatible with a range of labile
carbamate groups including Boc, Moz, and Fmoc
(Table 2, entries 3–5). The protocol tolerates substitu-
tion at C1, C2, C3, or C4 of the 4-pentenyl chain, often
with encouraging levels of diastereoselectivity (Table 2,
entries 6–11). Gold-catalyzed intramolecular hydro-
amination of alkenyl carbamates is also effective for
cyclization of unsubstituted 4-pentenyl derivatives
(Table 2, entry 12). Furthermore, AuI-catalyzed hydro-
amination of alkenyl carbamates can be applied to the
synthesis of aromatic and aliphatic heterobicyclic com-
pounds and to the synthesis of piperidine derivatives
(Table 2, entries 13–15). Notably, unsubstituted, C1-
monosubstituted, and monocyclic 4-pentenylbenzyl-
amines failed to undergo Pt-catalyzed hydroamination;
C2-monosubstituted 4-pentenylbenzylamines and 5-
hexenylbenzylamines undergo Pt-catalyzed cyclization
in modest yield.
8
9
R=H
R=Ac
60
60
22
18
91 (3.6:1)
63 (3.0:1)
10
100
39
93 (3.5:1)
Ar=4-C6H4OMe
11
12
13
100
100
100
55
68
47
91 (1.5:1)[c]
87 [c]
Information regarding the mechanisms of the AuI-
À
catalyzed addition of nucleophiles to C C multiple
bonds is limited. Teles et al. proposed an inner-sphere
mechanism for the AuI-catalyzed intermolecular addi-
tion of alcohols to alkynes on the basis of ab initio
calculations.[11] Conversely, stereochemical analysis of
the AuI-catalyzed intramolecular addition of alcohols
and activated methylene compounds to alkynes were in
accord with outer-sphere attackof the nucleophile on a
AuI-complexed alkyne.[9,12] On the basis of these latter
precedents, we favor a mechanism for the AuI-catalyzed
hydroamination of 4 involving outer-sphere attackof
the carbamate nitrogen atom on the Au-complexed
olefin of I coupled with loss of HCl to form the neutral
alkyl–gold complex II (Scheme 1). Protonolysis of the
59 [c]
14
15
100
100
30
26
95 (2.5:1)
84
[a] Isolated material of ꢀ95% purity. [b] Reaction run in the presence of H2O
(1 equiv). [c] Reaction run with 10 mol% of 6. Cbz=benzyloxycarbonyl, Boc=
tert-butoxycarbonyl, Moz=p-methoxybenzyloxycarbonyl, Fmoc=9-fluorenylme-
thyloxycarbonyl.
À
Au C bond of II would then release pyrrolidine 5 and
regenerate the cationic monophosphine gold catalyst.
In summary, we have developed an effective AuI-
catalyzed protocol for the intramolecular hydroamination of
alkenyl carbamates to form protected nitrogen heterocycles.
This protocol allows the intramolecular hydroamination of
unactivated olefins under milder conditions and with broader
substrate scope than was previously realized with late-
transition-metal catalyst systems.[17]
Experimental Section
5: A mixture of 4 (0.17 g, 0.45 mmol), 6 (12 mg, 0.022 mmol), and
AgOTf (6 mg, 0.02 mmol) in dioxane (0.45 mL) was degassed by
means of one freeze-pump-thaw cycle, pressurized with nitrogen, and
stirred at 608C for 18 h. The crude reaction mixture was purified by
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[15] For recent examples of the AuIII-catalyzed addition of carbon
and oxygen nucleophiles to alkenes and alkynes, see: a) A.
Hoffmann-Röder, N. Krause, Org. Lett. 2001, 3, 2537; b) A. S. K.
Hashmi, L. Schwarz, J.-H. Choi, T. M. Frost, Angew. Chem. 2000,
112, 2382; Angew. Chem. Int. Ed. 2000, 39, 2285; c) A. S. K.
Hashmi, Angew. Chem. 2000, 112, 3737; Angew. Chem. Int. Ed.
2000, 39, 3590; d) X. Yao, C.-J. Li, J. Am. Chem. Soc. 2004, 126,
6884; e) A. S. K. Hashimi, T. M. Frost, J. W. Bats, J. Am. Chem.
Soc. 2000, 122, 11553; f) T. Yao, X. Zhang, R. C. Larock, J. Am.
Chem. Soc. 2004, 126, 11164.
[16] Treatment of 4 with triflic acid (1 equiv) at 1008C for 24 h led to
complete decomposition of 4 with no detectable formation of 5.
Treatment of 4 with either AgOTf (5 mol%) or 6 (5 mol%)
alone in dioxane at 1008C for 24 led to no detectable
consumption of 4.
Scheme 1. Proposed mechanism for the AuI-catalyzed conversion of 4
into 5.
[17] For a related intermolecular hydroamination of 1,3-dienes, see
the previous Communication in this issue: C. Browder, C. He,
Angew. Chem. 2006, 118, 1776; Angew. Chem. Int. Ed. 2006, 45,
1744.
chromatography (hexanes/EtOAc 20:1) to give 5 (160 mg, 97%) as a
viscous, colorless oil.
Received: January 5, 2006
Published online: February 14, 2006
Keywords: alkenes · amines · gold · homogeneous catalysis ·
.
hydroamination
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