Gold-catalyzed intermolecular oxidation of terminal alkynes: Simple and efficient synthesis of α-mesyloxy ketones

Article abstract of DOI:10.1055/s-0033-1339337

A variety of terminal alkynes were efficiently converted into the corresponding α-mesyloxy ketones through gold-catalyzed intermolecular oxidation in the presence of 3,5-dichloropyridine N-oxide as the oxidant. The reaction is proposed to proceed via α-oxo gold carbene intermolecular O-H insertion. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1339337

LETTER
▌1809
letter
Gold-Catalyzed Intermolecular Oxidation of Terminal Alkynes: Simple and
Efficient Synthesis of α-Mesyloxy Ketones
Synthesis of α-Mesyloxy Ketones
Longyong Xie,a Zhiwu Liang,a Dong Yan,a,b Weimin He,*a Jiannan Xiang*a
a
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University,
Changsha 410082, P. R. of China
Fax +86(731)88821742; E-mail: wmhe@hnu.edu.cn; E-mail: jnxiang@hnu.edu.cn
b
Hunan Chemical Industry Vocation Technology Institute, Zhuzhou 412004, P. R. of China
Received: 21.04.2013; Accepted after revision: 10.06.2013
Over the past few years, the intra- and intermolecular ox-
Abstract: A variety of terminal alkynes were efficiently converted
idation of alkynes using pyridine/quinoline N-oxide3f,13
,
into the corresponding α-mesyloxy ketones through gold-catalyzed
intermolecular oxidation in the presence of 3,5-dichloropyridine N-
oxide as the oxidant. The reaction is proposed to proceed via α-oxo
gold carbene intermolecular O–H insertion.
amine N-oxide14, nitrones,3d,15 and sulfoxides16 as the ox-
Table 1 Optimization of the Reaction Conditionsa,21
Key words: alkynes, homogenous catalysis, gold, α-oxo gold car-
bine, α-mesyloxy ketones
O
[Au] (5 mol%)
[O] (1.3 equiv)
OMs
MsOH
+
chlorobenzene
1a
2a
Gold-catalyzed reactions are versatile tools for carbon–
carbon and carbon–heteroatom bond formation and,
hence, are the focus of intense synthetic attention.1 In par-
ticular, recent advances in the gold-catalyzed functional-
ization of alkynes have provided rapid and concise access
to complex chemical frameworks.2 Terminal alkynes are
readily available starting materials, and significant prog-
ress has been made in the gold-catalyzed functionalization
of terminal alkynes within the last decades.3
R
N
N
O–
4a R = H
4b R = Me
O–
R
4c R = 3-Br
4d R = 2,4-Cl2
4e R = 2,6-Cl2
4f R = 3,5-Cl2
4g R = 3,5-Br2
Entry
Catalyst
Oxidant Conditionsb Yield (%)c
The α-mesyloxy ketones are important intermediates in
organic synthesis.4 They often serve as precursors for var-
ious SN2 reactions in the preparation of α-functionalized
alkyl ketones.5 In addition, α-mesyloxy ketones are uti-
lized in photochemistry6 and ring contraction.7 For exam-
ple, in a total synthesis of pterosines B and C, the key step
is a photochemical ring closure of the α-mesyloxy ketone
forming the 1-indanone skeleton.8 Currently, the one-step
synthesis routes towards α-mesyloxy ketones are mainly
realized by oxidation of corresponding ketones using ei-
1
2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
IPrAuNTf2
BrettPhosAuNTf2
XPhosAuNTf2
Et3PAuNTf2
Cy3PAuNTf2
Cy3PAuNTf2
AgNTf2
4a
4b
4c
4d
4e
4f
4g
4f
4f
4f
4f
4f
4f
4f
4f
r.t., 8 h
r.t., 8 h
r.t., 8 h
r.t., 8 h
r.t., 8 h
r.t., 8 h
r.t., 8 h
r.t., 8 h
r.t., 8 h
r.t., 8 h
r.t., 8 h
r.t., 8 h
r.t., 8 h
r.t., 24 h
r.t., 24 h
21
30
47
33
48
61
55
30
44
51
51
79d
78
–
3
4
5
6
ther
CuO/MsOH,9
Ti(OCOMe)3/MsOH,10
or
7
PhI(OH)OMs.11 However, the former method uses stoi-
chiometric amounts of metal salts, whilst the latter suffers
from low regioselectivities. There are very few catalytic
methods for forming α-mesyloxy ketones in one step from
simple terminal alkynes. To the best of our knowledge,
only Xi described an acid-catalyzed reaction of alkynes
that gave α-mesyloxy ketones, while aliphatic alkynes
were not suitable substrates for the reaction.12 Thus, the
development of a simple and benign method to access α-
mesyloxy ketones remains a highly desired goal for or-
ganic chemists.
8
9
10
11
12
13e
14
15
–
–
a In vial; [1a] = 0.05 M.
b Monitored using TLC.
SYNLETT 2013, 24, 1809–1812
Advanced online publication: 01.08.2013
DOI: 10.1055/s-0033-1339337; Art ID: ST-2013-W0370-L
© Georg Thieme Verlag Stuttgart · New York
c NMR yield using diethyl phthalate as the internal reference.
d Isolated yield.
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
e Using 2 equiv of MsOH.

1810
L. Xie et al.
LETTER
idants represents a crucial advance in gold chemistry and served with AgNTf2 (Table 1, entry 14) or in the absence
offers efficient access to an array of synthetically versatile of a catalyst (Table 1, entry 15).
structures. In most cases, α-oxo gold carbene is proposed
Next, we explored the scope of the terminal alkynes for
the reaction with MsOH. As shown in Table 2, the reac-
tion was efficient with a series of phenylacetylenes. Both
electron-donating groups such as methyl, methoxy, and
as the reactive intermediate albeit with some exceptions.17
The generation of α-oxo gold carbenes via alkyne oxida-
tion provides a safe, step-economic, and scalable alterna-
tive to the formation of α-oxo metal carbenes/carbenoids
tertiary butyl groups (2b–d) and electron-withdrawing
via metal-catalyzed dediazotization of α-diazo ketones.18
groups such as fluoro, bromo, trifluoromethyl, and ester
groups (2–h) were all tolerated under the reaction condi-
Recently, our group has reported a simple method for the
one-step synthesis of α-chloro/bromomethyl ketones
tions, and good yields of the corresponding α-mesyloxy
through gold-catalyzed intermolecular oxidation of termi-
acetophenones were obtained. It is noteworthy that phen-
nal alkynes.13h In the course of this study, α-mesyloxy ke-
ylacetylenes bearing a substituent at the meta position (2i)
and substituents at ortho, meta, and para positions (2j)
tones were observed as minor side products. This
observation led us to investigate whether through tuning
were also suitable substrates for this reaction. However, 1-
of the reaction conditions, α-mesyloxy ketones could be
bromo-2-ethynylbenzene provided trace of target product
efficiently prepared. Herein we report a mild and efficient
gold-catalyzed intermolecular oxidation reaction of termi-
likely due to steric hindrance.19
To further exploit the generality of this catalytic reaction,
nal alkynes, affording the α-mesyloxy ketones in the pres-
aliphatic terminal alkynes were also investigated (Table 2,
ence of MsOH.
entries 10–19). Many synthetically important functional
groups were tolerated, including phenyl (2k), alkyl (2l),
As a preliminary study, phenylacetylene was treated with
1.3 equivalents of 8-methylquinoline N-oxide, 1.2 equiv-
chloro (2m), ester (2n), methanesulfonoxyl (2o), and
alents of MsOH, and
5 mol% Ph3PAuNTf2 in
ether (2p,q) groups. To our delight, the reaction with sub-
strates bearing a bulky group such as cyclohexenyl, cyclo-
hexyl, and cyclopropyl also proceeded smoothly (2r–t).
The reaction did not work with aliphatic internal alkynes
due to facile formation of enone.13b
chlorobenzene13f,j at room temperature (Table 1, entry 2).
Pleasingly, α-mesyloxy acetophenone was observed with
30% NMR yield via a gold-catalyzed intermolecular oxi-
dation process. To increase the reaction efficiency, a se-
ries of other oxidants (Table 1, entries 1 and 3–7) were
investigated. The employment of 3,5-dichloropyridine N-
oxide increase the yield to 61% (Table 1, entry 6). Next,
various cationic gold complexes were examined, and
In view of the mechanism of the previously reported ha-
lide abstraction by α-oxo gold carbenes13h and Cu(II)
complex mediated metal carbene insertion into the O–H
bonds of carboxylic acids,20 we have postulated a plausi-
ble mechanism. As shown in Scheme 1, coordination of
the cationic Au(I) to the alkyne facilitates the attack of
3,5-dichloropyridine N-oxide, which results in the forma-
tion of α-oxo gold carbene A. The gold carbene A inserts
into methanesulfonic O–H bonds via an oxygenium inter-
mediate (B); the gold enolate intermediate C could then
be protodeaurated to give 2 and cationic Au(I).
bulky
gold
catalysts,
such
as
IPrAuNTf2,
BrettPhosAuNTf2, and XPhosAuNTf2 (Table 1, entries 8–
10) showed lower reactivity than Ph3PAuNTf2. Among
the tested cationic gold species, Cy3PAuNTf2 (Table 1,
entry 12) was the best with 79% isolated yield. Further-
more, an increase in the amount of MsOH did not improve
the yield (Table 1, entry 13), and no product of 1a was ob-
O
OMs
R
R
2
1
O
H+
Au
Cl
Cl
Au
R
R
O
O
+
N
O–
Au+
H+
S
Me
O
C
Cl
O
Au
R
N+
O
O
Cl
O+
H
S
Me
R
O
O
O
B
Au+
Au
Au
R
R
MsOH
+
Cl
Cl
A
N
Scheme 1 Proposed reaction mechanism
Synlett 2013, 24, 1809–1812
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of α-Mesyloxy Ketones
1811
Table 2 Reaction Scopea,b
Cy3PAuNTf2 (5 mol%)
4f (1.3 equiv), MsOH (1.1 equiv)
O
OMs
R
chlorobenzene, r.t., 8 h
R
1
2
1
2
3
O
O
O
OMs
OMs
OMs
t-Bu
MeO
2b 81%
2c 84%
2d 82%
O
O
O
4
5
6
OMs
OMs
OMs
Br
F3C
F
2f 72%
2e 74%
2g 61%
O
O
O
7
8
9
MeO
OMs
OMs
OMs
MeO
OMe
MeO2C
2i, 72%
2h, 74%
2j, 64%
O
O
O
10
13
16
11
12
OMs
OMs
OMs
Cl
Ph
6
3
2k 55%
2m 65%
2l 58%
O
O
O
14
17
15
OMs
OMs
OMs
AcO
MsO
BnO
3
3
3
2n 52%
2o 53%
2p 57%
O
O
O
18
OMs
OMs
OMs
O
3
2q 51%
2s 66%
2r 63%
O
19
OMs
2t 67%
a In vial; [1] = 0.05 M.
b Isolated yield.
In conclusion, we have developed a one-step synthesis of
α-mesyloxy ketones from terminal alkynes with
Cy3PAuNTf2 as the catalyst and MsOH as the readily
available sulfonating agent. The α-oxo gold carbene inter-
molecular insertion into methanesulfonic O–H bonds is
very efficient and various functional groups are compati-
ble. In view of the relatively mild experimental conditions
and commercially available simple terminal alkynes, this
approach may find practical applications in organic syn-
thesis.
Acknowledgment
This work was supported by NSFC (21276068), Department of Sci-
ence and Technology Foundation of Hunan Province
(2010SK2001), Hunan Natural Science Foundation (11JJ5008), and
Training Program for Young Teachers in Hunan University.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
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Synlett 2013, 24, 1809–1812

1812
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LETTER
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N-Oxide 4f (0.39 mmol, 63.96 mg), MsOH (0.36 mmol,
34.60 mg) and Cy3PAuNTf2 (11.1 mg, 0.015 mmol) were
added to a solution of the alkyne 1 (0.30 mmol) in
chlorobenzene (6 mL) at r.t. The reaction mixture was stirred
at r.t., and the progress of the reaction was monitored by
TLC. The reaction typically took 8 h. Upon completion, the
mixture was concentrated, and the residue was purified by
chromatography on silica gel (eluent: hexanes–EtOAc) to
afford the desired product 2.
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2-Oxo-2-phenylethyl Methanesulfonate (2a)
Compound 2a was prepared in 79% yield according to the
general procedure and its spectroscopic data match well with
with those reported. 1H NMR (400 MHz, CDCl3): δ = 7.90
(d, J = 8.0 Hz, 2 H), 7.66 (t, J = 8.0 Hz, 1 H), 7.52 (t, J = 8.0
Hz, 2 H), 5.53 (s, 2 H), 3.30 (s, 3 H). 13C NMR (100 Mz,
CDCl3): δ = 191.09, 134.41, 133.45, 129.04, 127.76, 70.19,
39.15. IR (neat): 2956, 1702, 1560, 1338, 1156, 801 cm–1.
HRMS (EI): m/z calcd for C9H10O4S: 214.0300; found:
214.0297.
Synlett 2013, 24, 1809–1812
© Georg Thieme Verlag Stuttgart · New York

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