Gold-catalyzed intramolecular aminoarylation of alkenes: C-C bond formation through bimolecular reductive elimination

Article abstract of DOI:10.1002/anie.201002739

(Chemical equation presented) Gold-ilocks and the 3 mol% catalyst: Bimetallic gold bromides allow the room temperature aminoarylation of unactivated terminal olefins with aryl boronic acids using Selectfluor as an oxidant. A catalytic cycle involving gold (I)/gold(III) and a bimolecular reductive elimination for the key C-C bond-forming step is proposed, dppm= bis(diphenylphosphanyl) methane.

Full text of DOI:10.1002/anie.201002739

Angewandte
Chemie
DOI: 10.1002/anie.201002739
Gold Catalysis
À
Gold-Catalyzed Intramolecular Aminoarylation of Alkenes: C C
Bond Formation through Bimolecular Reductive Elimination**
William E. Brenzovich, Jr., Diego Benitez, Aaron D. Lackner, Hunter P. Shunatona,
Ekaterina Tkatchouk, William A. Goddard, III, and F. Dean Toste*
Table 1: Catalyst screen for the aminoarylation reaction.[a]
The utility of homogeneous gold complexes as carbophilic p-
acids has been well-established, with numerous reports of
gold-catalyzed reactions that were initiated by addition of
nucleophiles into unsaturated carbon–carbon bonds.[1]
Although protodeauration is common, several reactions
Entry
Catalyst (mol%)
Yield of 2 [%][b]
have been developed in which the resulting organogold
intermediate was intercepted. For example, nucleophilic
reagents have been employed to intercept cationic organo-
gold intermediates that were derived from reactions with
p bonds.[2] In contrast, reactions involving neutral organogold
intermediates are terminated by reaction of the resulting
carbon–gold bond with an electrophile. Although the electro-
phile is often a proton, gold(I)-catalyzed carboheterofunc-
tionalization reactions using carbon-based electrophiles have
been reported.[3] On the basis of recent reports of gold-
catalyzed oxidative transformations,[4] we envisioned that the
oxidized analogues of these gold(I) intermediates might also
be susceptible to reactive nucleophilic reagents.
1
2
3
4
5
6
7
8
Ph3PAuCl (5)
Ph3PAuOTf (5)
Ph3PAuOBz (5)
Ph3PAuBr (5)
24
<5
18
47
<5
Ph3PAuI (5)
[(Ph3P)2Au]BF4 (5)
[dppm(AuBr)2] (3)
[dppb(AuBr)2] (3)
22
81 (72)[c]
26[c]
[a] Reactions run in a sealed vial at 0.05m in 1. [b] Yields determined by
1H NMR with diethyl phthalate as an internal standard. [c] Yield of
isolated product. dppm=bis(diphenylphosphanyl)methane, dppb=
bis(diphenylphosphanyl)butane, Ts=4-toluenemethanesulfonyl.
In line with our efforts in the area of gold-catalyzed
hydroamination reactions,[5,6] we hypothesized that oxidized
organogold intermediates that are derived from addition of
an amine to a p bond might react with nucleophilic boronic
acids in an intramolecular aminoarylation reaction.[7] Whilst
our initial studies using allenyl tosylamides were unsuccessful,
we were encouraged to find that the Ph3PAuCl-catalyzed
reaction of alkenyl tosylamide 1 with excess phenylboronic
acid and Selectfluor provided a modest yield of the desired
aminoarylation product, 2 (Table 1, entry 1). Using a more
cationic gold species, such as Ph3PAuOTf (Table 1, entry 2),
led to diminished reactivity. On the basis of our previous
observation of counterion effects in gold-catalyzed reac-
tions,[5] we examined the impact of the counterion on the
aminoarylation reaction. Whilst the use of Ph3PAuOBz as a
catalyst resulted in decreased conversion (Table 1, entry 3),
Ph3PAuBr led to a significant increase in the yield of 2
(Table 1, entry 4). The corresponding gold(I) iodide (Table 1,
entry 5) provided 2 in only trace amounts, as the iodide itself
is likely susceptible to oxidation by Selectfluor.
To optimize the reaction further, we sought to identify the
active gold species. The combination of either Ph3PAuCl or
Ph3PAuBr with Selectfluor and PhB(OH)2 led to the forma-
tion of a major signal in the 31P NMR spectrum at d =
44.28 ppm, which we identified as [(Ph3P)2Au]+. Moreover,
in situ monitoring of the reaction mixture by 31P NMR
spectroscopy showed this cationic complex to be the domi-
nant gold species in solution during the catalytic reaction;
however, independently prepared [(Ph3P)2Au]BF4 was found
to produce 2 in inferior yield (Table 1, entry 6) to those
obtained when Ph3PAuBr was employed as a catalyst. As
[*] Dr. W. E. Brenzovich, Jr., A. D. Lackner, H. P. Shunatona,
Prof. F. D. Toste
I
III
À
strong aurophilic interactions are maintained for Au Au
species,[8] we reasoned that the use of bimetallic[9] gold
complexes as catalysts might minimize the formation of this
type of bisphosphinogold(I) species. We were delighted to
find that [dppm(AuBr)2] was an excellent catalyst at room
temperature (Table 1, entry 7).[10,11]
Department of Chemistry, University of California, Berkeley
Berkeley, CA 94720 (USA)
Fax: (+1)510-643-9480
E-mail: fdtoste@berkeley.edu
Dr. D. Benitez, Dr. E. Tkatchouk, Prof. W. A. Goddard, III
Materials and Process Simulation Center, California Institute of
Technology
The optimized conditions appear to tolerate a wide
variety of sulfonamides and to be independent of substitution
pattern (Table 2); in addition, trifluoroacetamides are rea-
sonable substrates for the reaction (Table 2, entry 1). The
cyclization provides N-protected pyrrolidines at room tem-
perature, even for substrates that do not have the benefit of
the Thorpe–Ingold effect (Table 2, entry 2). The ability to
form six-membered rings (Table 2, entry 3) is notable, with
Pasadena, CA 02215 (USA)
[**] F.D.T. gratefully acknowledges NIHGMS (R01 GM073932-04S1),
Novartis, and Amgen for funding and Johnson Matthey for a
generous donation of AuCl3. The MSC computational facilities were
funded by grants from ARO-DURIP and ONR-DURIP.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201002739.
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Table 2: Substrate scope for the aminoarylation reaction.
poor boronic acids reacted sluggishly under the standard
room temperature conditions, but functional yields were
obtained by heating the reaction mixture to 408C. Sensitive
moieties, such as aldehydes, readily withstood the mild
reaction conditions. Reduced yields were observed with
highly electron-rich coupling partners, such as para-methox-
yphenylboronic acid, owing to competing oxidation of the
boronic acid by Selectfluor.
Entry
1
Substrate
Product
T [8C]
Yield [%]
51
60
Several possibilities exist for the mechanism of this
transformation. First, we considered the initial cyclization
event. Treatment of 1 with neutral phosphinegold(I) halide
complexes in the absence of Selectfluor produced no detect-
able reaction. Cationic AuI species are typically required for
addition to p bonds; however, in this case, cationic triphenyl-
phosphinegold(I) complexes failed to catalyze the reaction
(Table 1, entry 2). Moreover, treatment of alkylgold(I) com-
plex 30[12] with phenylboronic acid and Selectfluor failed to
produce pyrrolidine 2 [Eq. (1)]. Therefore, we surmised that
oxidation of AuI into AuIII must precede the aminoauration
step.
2
3
4
RT
40
RT
70
82
72[b]
5
RT
72[c]
6
7
8
RT
40
40
92[d]
64
63
[a] Yield of isolated product. [b] d.r.=1.5:1. [c] d.r.=1.1:1. [d] d.r.=1.8:1.
TFA=trifluoroacetic acid.
Next, we considered the potential transmetalation of the
phosphinegold(I) halide with the boronic acid as the initial
step in the catalytic cycle. However, the combination of
Ph3PAuCl and phenylboronic acid in acetonitrile, even after
several hours both at room temperature and 608C, gave no
Ph3PAuPh as judged by 31P NMR spectroscopy.[13] This
observation suggests that any transmetalation likely follows
À
only a slight increase in temperature required. We have also
achieved mild access to functionalized 2,3-dihydroindole and
1,2,3,4-tetrahydroisoquinoline products (Table 2, entries 7
and 8). The reaction tolerated a variety of sulfonamide
protecting groups and boronic acids (Table 3), both electron
poor and electron rich. More-hindered and more-electron-
oxidation and the or subsequent formation of a AuIII
intermediate, thereby allowing for the favorable formation of
F
À
a B F bond.
À
In examining the mechanism of C C bond formation, we
assessed the possibility of a traditional reductive elimination
pathway from a gold(III)–phenyl intermediate, analogous to
the related transition-metal-catalyzed oxidative cyclization
reactions.[7] Reductive eliminations from gold(III)–alkyl and
gold(III)–aryl complexes have been reported, but typically
require elevated temperatures,[14] whereas our reaction occurs
readily even at room temperature. Furthermore, we found
that whilst Ph3PAuPh was a competent catalyst for the
reaction,[15] treatment of 5a with stoichiometric Ph3PAuPh
and Selectfluor in the absence of boronic acid led to only trace
product formation (Table 4, entry 1). Addition of a phenyl-
borate recovers the reaction, and provides 6 in reasonable
yields (Table 4, entry 2). Moreover, the reaction of 5a with
different boronic acids and Ph3PAuPh produced adducts 25
and 28 derived from transfer from the arylboronic acid and
not from the phenylgold species, almost exclusively, regard-
less of the electronic properties of the boronic acid (Table 4,
entries 3 and 4).
Table 3: Sulfonyl and boronic acid scope for the aminoarylation
reaction.[a]
Entry
R1
R2
Product T [8C] Yield [%]
1
2
3
4
5
6
7
8
4-MeOC6H4 (5b)
4-BrC6H4 (5c)
H
H
H
H
3-F
19
20
21
22
23
24
25
26
27
28
29
RT
RT
RT
40
40
40
40
40
40
RT
RT
57
79
75
75
75
56
83
77
68
81
17[b]
2-O2NC6H4 (5d)
4-O2NC6H4] (5e)
4-Me-C6H4 (5a)
4-MeC6H4 (5a)
4-MeC6H4 (5a)
4-MeC6H4 (5a)
4-MeC6H4 (5a)
4-MeC6H4 (5a)
4-MeC6H4 (5a)
2-Cl
4-CO2Me
2-CO2Me
4-CHO
4-Me
4-MeO
9
10
11
À
These observations suggest that formation of the C C
bond by a reductive elimination from phenylgold(III) inter-
[a] Reactions conditions: 5 (100 mmol), boronic acid (200 mmol), Select-
fluor (150 mmol), and [dppm(AuBr)2] (3 mmol) in MeCN (1.0 mL) for
12 h. [b] Recovered 5a=74%.
mediate 32 is unlikely, and that, in the case of Ph3PAuPh, the
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À
Table 4: C C bond formation with Ph3PAuPh.
Entry
Ar-B(OH)2
Yield [%][a]
Ar/Ph
1
2
3
4
–
<5
52
58
37
–
–
94:6
93:7
Ph-B(OH)2
4-MeC6H4-B(OH)2
4-MeO2CC6H4-B(OH)2
[b]
1
[a] Yield determined by H NMR spectroscopy with diethyl phthalate as
an internal standard. [b] Reaction carried out at 408C.
Scheme 2. Examination of the reaction stereochemistry using deute-
rium labeling.[18]
phenyl group acts as a spectator ligand. Therefore, we
propose that interaction of the boronic acid with alkylgold-
(III) fluoride intermediate 31 does not result in transmetala-
tion to 32, but instead induces a bimolecular reductive
Selectfluor. Ligand and halide effects played a dramatic role
in the development of an exceptionally mild catalyst system
for the addition to alkenes. Finally, although it is tempting to
invoke a mechanism for reductive elimination similar to that
proposed for other transition-metal complexes, our exper-
À
elimination. In this hypothesis, the B F interaction is key
for the reductive elimination step, as it increases the
nucleophilicity of the boronic acid and the electrophilicity
À
of the carbon gold(III) moiety. Although the formation of
À
the boronate and the subsequent nucleophilic displacement of
the gold moiety can occur as separate steps, we envision that
these events occur simultaneously via five-centered transi-
tion-state 33 (Scheme 1).[16]
imental studies suggest that the C C bond-forming reaction
occurs through a bimolecular reductive elimination. Studies
directed towards the application of this catalyst system and
reactivity paradigm towards the development of further
transformations are underway in our laboratory.
Received: May 6, 2010
Published online: July 2, 2010
À
Keywords: alkenes · C C bond formation · cyclization · gold ·
homogeneous catalysis
.
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À
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À
À
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À
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