Electrophilicity of α-oxo gold carbene intermediates: Halogen abstractions from halogenated solvents leading to the formation of chloro/bromomethyl ketones

Article abstract of DOI:10.1039/c2ob25235j

α-Oxo gold carbenes generated via intermolecular oxidation of terminal alkynes are shown to be highly electrophilic and can effectively abstract halogen from halogenated solvents such as 1,2-dichloroethane or 1,2-dibromoethane. Chloro/bromomethyl ketones are prepared in moderate efficiencies in one step using Ph₃PAuNTf₂ as the catalyst and 8-methylquinoline N-oxide as the oxidant.

Full text of DOI:10.1039/c2ob25235j

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Electrophilicity of α-oxo gold carbene intermediates: halogen abstractions
from halogenated solvents leading to the formation of chloro/bromomethyl
ketones†
Weimin He,a Longyong Xie,a Yingying Xu,a Jiannan Xiang*a and Liming Zhang*b
Received 1st February 2012, Accepted 15th February 2012
DOI: 10.1039/c2ob25235j
dichloroethane (DCE) and 1,2-dibromoethane; moreover, a one-
step synthesis of versatile chloro/bromomethyl ketones from
terminal alkynes is developed.
Recently some of us have developed a practical protocol for
the generation of α-oxo gold carbene A via gold-catalyzed inter-
molecular alkyne oxidation,3b–d,f,g and derivatized pyridine/qui-
noline N-oxides are the oxidants of choice. Notably, this
approach circumvents the use of α-diazo compounds, typically
employed for accessing α-oxo metal carbenes.6
α-Oxo gold carbenes generated via intermolecular oxidation
of terminal alkynes are shown to be highly electrophilic and
can effectively abstract halogen from halogenated solvents
such as 1,2-dichloroethane or 1,2-dibromoethane. Chloro/
bromomethyl ketones are prepared in moderate efficiencies
in one step using Ph3PAuNTf2 as the catalyst and 8-methyl-
quinoline N-oxide as the oxidant.
Among various types of gold catalysis developed in the past
decade,1 gold-catalyzed oxidation of alkynes, either intramolecu-
larly2 or intermolecularly,3 has contributed significantly to the
diversity and the versatility of gold chemistry and offers efficient
access to an array of synthetically versatile structures. In most
cases, α-oxo gold carbene A is proposed as the reactive inter-
mediate (Scheme 1). Albeit with exceptions,3a,e,4 its intermedi-
acy seems to offer the only reasonable rationale for the reaction
outcome in many instances. Trapped mostly by optimally teth-
ered nucleophiles or nucleophilic solvent,3g its reactivity is still
not well understood, even to the extent of its electrophilicity.
Only a few examples of formal C–H insertions and cyclopropa-
nations3h,k are realized under optimal circumstances.5 Herein, we
disclose that the gold carbene intermediate is highly electrophilic
and can abstract halides from halogenated solvents such as 1,2-
In some of our previous studies,4 we noticed the formation of
small amounts of α-chloromethyl ketones when DCE was the
reaction solvent. For example, 1-chlorododecan-2-one (i.e., 2a)
was formed in 8% NMR yield when dodec-1-yne was treated
with 8-methylquinoline N-oxide3c (i.e., 4b) in DCE (Table 1,
entry 1). This reaction could be improved when a slight
excess of MsOH was introduced (entry 2) and further by
running the reaction at ambient temperature (entry 3).
Mesylate 3a was also formed but in small quantities,
consistent with our previous observation.3b The origin of
the chloride, although somewhat unexpected, was apparently
from DCE, the reaction solvent. Moreover, chloride
abstraction from methylene chloride by the same gold carbene
also occurred albeit with a decreased efficiency (entry 4). Further
evidence was provided by the formation of 2-chloroethyl mesy-
late in the case of entry 3, which identity was confirmed upon
isolation.
The reaction outcome is rationalized in Scheme 2: the α-oxo
gold carbene intermediate B is first formed via intermolecular
alkyne oxidation and then behaves as a highly electrophilic
species, abstracting a chloride from the solvent via a chloronium
intermediate (i.e., C); the gold enolate intermediate D could then
be protodeaurated to form 2a; the solvent molecule, upon the
loss of Cl−, would become ethylene chloronium, which is then
attacked by mesylate to form the observed 2-chloroethyl mesy-
late. Alternatively, the chloronium intermediate C might be first
protonated to form the chloronium E, which could be attacked
by mesylate to form either 2a and 2-chloroethyl mesylate or 3a,
depending on the approaching point of the nucleophile. In
addition, the gold carbene B might insert into mesylic acid to
afford 3a.
Scheme 1 Gold-catalyzed alkyne oxidation.
aCollege of Chemistry and Chemical Engineering, State Key Laboratory
of Chemo/Biosensing and Chemometrics, Hunan University, Changsha,
410082, P.R. of China. E-mail: jnxiang@hnu.edu.cn
bDepartment of Chemistry and Biochemistry, University of California,
Santa Barbara, California 93106, United States. E-mail: zhang@
chem.ucsb.edu; Fax: +1 (805)893-4120; Tel: +1 (805)893-7392
†Electronic supplementary information (ESI) available: Experimental
1
procedures, compound characterizations, and H and 13C NMR spectra.
See DOI: 10.1039/c2ob25235j
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Table 1 Chloride abstraction by a α-oxo gold carbenea
Yieldb [%]
Entry
Gold catalyst
Oxidant
Acid (1.1 eq)
Reaction conditions
2a
3a
1
2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
IPrAuNTf2
4b
4b
4b
4b
4a
4c
4d
4e
4b
4b
4b
—
60 °C, 8 h
60 °C, 8 h
RT, 8 h
RT, 8 h
RT, 8 h
RT, 8 h
RT, 8 h
RT, 8 h
RT, 8 h
RT, 8 h
RT, 8 h
8
0
6
5
6
MsOH
MsOH
MsOH
MsOH
MsOH
MsOH
MsOH
MsOH
MsOH
MsOH
39
63cd
41
60
21
24
39
19
51
4
3
4e
5
5
6
7
8
9
10
11
11
15
14
11
13
13
f
(RO)3PAuNTf2
Au(III)g
a In vial; [1a] = 0.1 M. b Estimated by 1H NMR spectroscopy using diethyl phthalate as an internal reference. c Isolated yield of 63%.
d MsOCH2CH2Cl was formed in 46% yield. e CH2Cl2 as solvent. f R = 2,4-(t-Bu)2Ph. g Dichloro(2-picolinato)gold(III).
dione reacts with DCE and DCM to form 2-chloro-3-hydroxy-
cyclohex-2-enone (i.e., 5, eqn (1)). The chloronium F is the pro-
posed intermediate. Later, Lee showed that this type of rhodium
carbenoids can abstract chloride from a range of other sources
including acyl chloride, alkyl/benzyl halides besides halogenated
solvents.7c In the case of DCM, however, he reported the iso-
lation of dichloride 6 in 79% yield; the same result was obtained
by Müller et al.7d It is important to point out that in these studies
the highly electrophilic rhodium carbene/carbenoid intermediates
are flanked by two electron-withdrawing carbonyl groups. In
comparison, the gold carbene of type B, capable of similar chlor-
ide abstraction, has only one α-carbonyl group. This indicates
that gold is in general less capable of back bonding9 than
rhodium, therefore leading to a more electrophilic carbene center
than that of a related rhodium species. An alternative explanation
Scheme 2 Proposed reaction mechanism.
for the high electrophilicity of B by invoking a MsOH protona-
tion of its oxo group prior to chloride abstraction is unlikely as
2a was formed without acid (see Table 1, entry 1) and, moreover,
such a protonated intermediate, if formed, would most likely
lead to mesylate 3a due to trapping by the counter anion, i.e.,
MsO−, which should be more nucleophilic than the neutral
solvent. Other α-oxo metal carbenes capable of this type of
chloride abstraction have been reported by Dias et al.7b and later
Maseras and co-workers7e (Ag) and Davies and Albrecht2h (Pt),
ð1Þ
confirming that later transition metals (in relation to rhodium)
tends to be poor in back bonding.
Further reaction conditions optimization using different N-
oxides (Table 1, entries 5–8) and different gold catalysts
(Table 1, entries 9–11) did not lead to an improved yield.
Notably, many reactions involving metal carbene/carbenoid
intermediates are performed in DCM or DCE,6 but only a few
instances of chloride abstraction7,8 have been documented to
date. In 1995, Pirrung et al.7f reported that the rhodium carbe-
noid generated via dediazotization of 2-diazocyclohexane-1,3-
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Table 2 The reaction scopeab
Conclusions
We have reported a surprising halide abstraction by α-gold car-
benes generated via gold-catalyzed intermolecular oxidation of
terminal alkynes. Synthetically useful chloro/bromomethyl
ketones can be prepared in one-step from terminal alkynes.
Although the reaction efficiency is moderate, this method may
find its usage in scenarios where functional group compatibility
is critical, by masking the reactive halomethyl ketone as a term-
inal alkyne. Importantly, the strong electrophilicity of the gold
carbene intermediates reveals that gold in general is less effective
in back bonding than rhodium but perhaps similar to Ag. This
conclusion forecasts that the chemistry of α-oxo gold carbenes,
yet to be fully studied, could be very different from the well-
studied Rh counterpart and may provide new opportunities for
methodology development, especially via the alkyne oxidation
strategy.
1
2
3
2b, 58%
4
2c, 42%
5
2d, 62%
6
2e, 55%
7
2f, 65%
8
2g, 53%
9
2h, 51%
10
2i, 56%
11
2j, 70%
12
WH, LX, YX and JX are grateful for the financial support of
Department of Science and Technology Foundation of Hunan
Province (2009WK4005), Hunan Nature Science Foundation
(11JJ5008) and Changsha Science and Technology (K082152-
31). LZ and WH is grateful of the generous financial support by
NSF (CAREER CHE-0969157).
2k, 60%
13
2l, 41%
2m, 43%
14c
15c
2n, 37%
2o, 68%
2p, 60%
16c
17c
18c
Notes and references
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2s, 42%
a Reaction conditions: [1] = 0.1 M. b Isolated yield are given. c Using
BrettPhosAuNTf2 as the gold catalyst.
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using dibromoethane as the solvent, this alkyne oxidation strat-
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ketones (entries 14–18). In all the cases, yields were mostly
moderate but synthetically serviceable, reflecting the reactive
nature of the α-oxo gold carbene intermediates. This reaction did
not work with aliphatic internal alkynes due to facile enone
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