Oxidative coupling of terminal alkyne with α-hydroxy ketone: An expedient approach toward ynediones

Article abstract of DOI:10.1021/ol502298a

An efficient and mild copper-catalyzed one-pot approach toward ynediones has been established. A variety of ynediones were constructed directly through oxidative coupling of alkyne with α-hydroxy ketone. Oxygen-oxidizing and neutral conditions in one-pot for a wide range of substrates including natural product derivatives make this transformation highly efficient and practical. On the basis of control experiments, in situ IR measurements, and isotopic labeling experiments, a plausible mechanism involving intermediate phenylglyoxal was drawn. Applications by synthesis of various heterocycles were also investigated.

Full text of DOI:10.1021/ol502298a

Letter
pubs.acs.org/OrgLett
Oxidative Coupling of Terminal Alkyne with α‑Hydroxy Ketone: An
Expedient Approach toward Ynediones
Zeguang Zhang† and Xuefeng Jiang*,†,‡
†Shanghai Key Laboratory of Green Chemistry and Chemical Process, Department of Chemistry, East China Normal University,
Shanghai 200062, P. R. China
‡Beijing National Laboratory for Molecular Sciences (BNLMS), Beijing 100190, P. R. China
S
* Supporting Information
ABSTRACT: An efficient and mild copper-catalyzed one-pot
approach toward ynediones has been established. A variety of
ynediones were constructed directly through oxidative coupling of
alkyne with α-hydroxy ketone. Oxygen-oxidizing and neutral
conditions in one-pot for a wide range of substrates including natural product derivatives make this transformation highly
efficient and practical. On the basis of control experiments, in situ IR measurements, and isotopic labeling experiments, a plausible
mechanism involving intermediate phenylglyoxal was drawn. Applications by synthesis of various heterocycles were also
investigated.
nediones are more densely functionalized electrophiles than
ynones. Continuous two-carbonyl and alkynyl groups make
We commenced our study by investigating 2-hydroxy-1-
phenylethanone 1a coupling with phenylacetylene 1b. The
reaction was first performed in the presence of copper acetate
and silver nitrate at 80 °C in dioxane under air, which generated
the desired product 1ab in 37% yield (Table 1, entry 1). Acetic
acid was added to avoid Glaser coupling of 1b (Table 1, entry 2).
After a series of copper salts were tested, copper(I) thiophene-2-
carboxylate was demonstrated to be the best choice (Table 1,
entry 3). Considering solvents, toluene had an inhibiting effect
on side products (Table 1, entries 4−6). Compound 1b was
Y
ynedione a powerful synthetic precursor that could be easily
transformed to a series of specific heterocycles.1,2 However,
because of a lack of ready and practical preparation, the
application of ynediones remains rarely explored. To the best of
our knowledge, most of the reported approaches toward
ynediones employ Castro−Stephens coupling3 involving glyox-
ylyl chlorides and terminal alkynes (Scheme 1).4 Muller’s group
̈
Scheme 1. Ynedione Synthesis
Table 1. Optimization for the Synthesis of Ynediones
e
entry
[Cu]
[Ag]
additive
solvent
note yield (%)
1
2
3
4
5
6
7
8
9
Cu(OAc)2
Cu(OAc)2
CuTC
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
none
none
dioxane
dioxane
dioxane
MeCN
THF
a
a
a
a
a
a
b
b
b
37
AcOH
AcOH
AcOH
AcOH
AcOH
none
53
63
CuTC
trace
trace
64
CuTC
CuTC
toluene
toluene
toluene
toluene
c
CuTC
77
CuTC
none
none
82
d
CuTC
none
none
85
established a convenient method via in situ glyoxylation of
electron-rich heteroaromatic nucleophiles and α-keto carboxylic
acids with oxalyl chloride. The oxidative coupling5 of α-hydroxy
ketone and terminal alkyne6,7 is supposed to be an efficient and
direct method to ynedione, which is also a challenge. Terminal
alkyne could barely avoid Glaser coupling8 in the presence of
oxidant and copper catalyst when coupled with ketones.
Fortunately, we found a carbon−carbon cleavage system,
showing that α-hydroxy ketone is a fantastic radical precursor
at the α-position, which may oxidatively couple with terminal
alkyne for the generation of ynediones.9
a
Reaction conditions: 1a (0.2 mmol), 1b (2.0 equiv), AgNO3 (30 mol
%), additive (1.0 equiv), and [Cu] (20 mol %) were stirred at 80 °C in
solvent (2 mL) for 8 h under air. Reaction conditions: 1a (0.2 mmol)
and CuTC (10 mol %) were stirred at 90 °C in solvent (2 mL) for 2 h
under O2, then 1b (5.0 equiv) was added. The system was heated for
b
c
d
another 4 h under O2. 4.0 equiv of 1b was added. 0.2 mmol of 1a in
4 mL of toluene. Isolated yields.
e
Received: June 22, 2014
© XXXX American Chemical Society
A
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Letter
added after 1a was oxygenated under oxygen atmosphere, and
the yield was increased to 77% (Table 1, entry 7). The addition of
silver nitrate or copper acetic acid, which probably helps to
liberate Cu+ from the formed alkynyl copper to oxidation of 1a,
produced no improvement in this reaction. Concentration of 1a
and 1b was crucial as well (Table 1, entries 8 and 9). Finally, an
85% yield could be achieved under the conditions of 0.05 M 1a in
toluene.
alkyne substrate was applied (37ab). Alkyl acetylenes containing
phenyl or heterocycle using ester as a linkage produced the
products as well (38ab−40ab).
a
Table 3. Scope of Alkynes
With the optimized conditions identified, a series of α-hydroxy
ketones were investigated (Table 2). It should be pointed out is
a
Table 2. Scope of α-Hydroxy Ketones
a
Standard conditions: 1a (0.2 mmol) and CuTC (10 mol %) were
stirred at 90 °C in solvent (4 mL) for 2 h under O2, and then terminal
alkyne (5.0 equiv) was added. The system was heated for another 4 h
b
c
under O2. 2.0 equiv of benzoquinone was added. 50 mol % of CuTC
was added.
a
Standard conditions: α-hydroxy ketone (0.2 mmol) and CuTC (10
The late-stage modification of a bioactive molecule is highly
important for medical chemistry studies. Notably, 3-ethynyles-
trone 22b containing carbonyl group and four continuous chiral
centers resulted in the desired product in 87% yield by this
method. 3α-(But-3-ynyloxy)-5-cholestene 23b with an alkenyl
group and eight chiral centers produced a 75% yield of the
desired product. Moreover, 1,2:5,6-di-O-isopropylidene-α-D-
glucofuranose-3-yl pent-4-ynoate 24b with sensitive sugar acetal
and acetone-protecting groups was also tolerated and produced
the corresponding products in 65% yield, which showed great
potential for drug late-stage modification (Scheme 2).11
mol %) were stirred at 90 °C in the solvent (4 mL) for 2 h under O2,
and then 1b (5.0 equiv) was added. The system was heated for another
b
c
4 h under O2. 2 mmol scale of 1a. 10 mmol scale of 1a.
that when 1a was scaled up to 2 mmol (272 mg), the yield
remained excellent. Even when the reaction performed on a 10
mmol (1.36 g) scale of 1a, a 62% yield was obtained (Table 2,
entry 1). α-Hydroxy ketones both with electron-donating and
electron-withdrawing groups could be successfully converted to
the corresponding ynediones in moderate-to-excellent yields
(2ab−5ab). α-Hydroxy ketones with methyl-substituted at the
o-, m-, and p-position on the aryl ring did not show strong steric
effects (6ab−8ab). Not only inactive halogen substituted
substrates bearing F and Cl but also copper-active substrates
bearing Br and I could produce good yields (9ab−12ab).
Further, this method could be applied to a variety of condensed
rings and heterocycles, such as naphthalene (13ab and 14ab),
furan (15ab), thiophene (16ab and 17ab), benzofuran (18ab),
2,3-dihydrobenzofuran (19ab), and benzothiophene (20ab).
After the great tolerance of α-hydroxy ketones was
demonstrated, different functionalized terminal alkynes also
performed well. In fact, not only arynes but also alkyl acetylenes,
which show the mismatchment in other methodologies, worked
well in the transformation. Aryne with methyl and methoxyl
groups offered moderate to excellent yields (21ab and 22ab).
Long-chain alkyl-substituted alkynes, such as 1-hexyne (23ab)
and 1-octyne (24ab), could also afford a moderate yield after p-
benzoquinone was added to promote the oxidative process.10
Cycloalkane-substituted alkynes, such as cyclopropyl (25ab) and
cyclohexyl (26ab) acetylenes, could be transformed to the
desired products in 69% and 50% yield, respectively. Terminal
alkyl acetylenes bearing various hydroxyl protection groups,
including TBS, TBDPS, Bn, THP, and allyl (27−31ab), were all
compatible in this reaction to afford the desired products, which
showed great application potential in organic synthesis. Phenyl,
phthalimide, chlorine, TES, and ester groups (32ab−36ab) were
tolerated in the present reaction system as well. Only one alkynyl
was transformed to the ynedione when disubstituted terminal-
Scheme 2. Late-Stage Modification
To gain mechanistic insight into this one-pot synthesis of
ynediones, several control experiments were conducted. When
1a was subjected to standard conditions, we observed that an
intermediate formed before 1b was added (Scheme 3, eq 1).
Through crude 1H NMR, it presented a mixture of phenylglyoxal
1d, phenylglyoxal monohydrate 1c, and other side products,
which indicated that the intermediate was not stable. When the
copper catalyst was removed, or oxygen was changed to nitrogen
B
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Letter
measurements were conducted again to observe the trans-
formation from 1c to 1ab (Supporting Information). Both the
control experiments and in situ IR measurements demonstrated
the active intermediate is phenylglyoxal 1d. If the reaction was
conducted under nitrogen after the oxidation of 1a, it resulted in
a 34% yield of the desired product 1ab without other
intermediates being observed (Scheme 4, eq 3).
Scheme 3. Control Experiments for Intermediate Formation
Isotopic-labeling experiments showed that the starting ma-
terial α-hydroxy ketone 1a barely underwent oxygen atom
exchange with water (Scheme 5, eq 1), while 26% of the product
Scheme 5. Isotopic Labeling Experiments
under standard conditions, the reaction would not proceed
(Scheme 3, eqs 2 and 3), which illustrates that 1a was oxidized
with the cooperation of copper and oxygen.12 Furthermore, this
reaction was respectively oxidized by catalytic copper(II) (10
mol %) under oxygen atmosphere and stoichiometric copper(II)
(4.0 equiv) under nitrogen atmosphere (Scheme 3, eqs 4 and 5),
which showed that the former provided a much better result
(40% and 5%). This comparison indicated that oxygen played
multiple roles in the reaction process rather than only oxidizing
copper from low to high valence.
ynedione 1ab had been exchanged by 18O from H218O (Scheme
5, eq 2). Furthermore, two isotopic labeling experiments
comparing H218O (2.0 equiv) and 18O2 were also performed.
When the reaction was launched in the presence of H218O (2.0
equiv), 1ab-16O2 (47%), 1ab-18O16O (27%), and 1ab-18O2 (4%)
were detected (Scheme 5, eq 3). When the reaction was
conducted under 18O2 atmosphere, 1ab-16O2 (62%) and
1ab-18O16O (18%) were detected (Scheme 5, eq 4). It indicated
that the oxygen atom of the ynediones originated from α-
hydroxy ketones and water, not from oxygen gas.
To further confirm the unstable intermediate, in situ IR
measurements were attempted to observe the whole process of
this reaction (Figure 1). Phenylglyoxal intermediate with two
On the basis of the above results, a plausible mechanism was
drawn (Scheme 6). The oxidation of hydroxyl underwent in two
probable paths. In path A, copper alkoxide 1g produced binuclear
copper(II) peroxide 1h with the help of oxygen. Homolytic
cleavage followed by hydrogen atom abstraction afforded 1d and
the hydroxy copper(I) species. After rapid exchange between the
hydroxy ligand and alcohol 1a, along with the loss of a water
molecule, the copper alkoxide 1g was regenerated.13 In path B, 1a
Scheme 6. Plausible Mechanism
Figure 1. In situ IR measurements.
clear peaks (characteristic stretch at ν = 1552 and 1429 cm−1)
formed gradually after copper(I) thiophene-2-carboxylate was
added to a solution of 1a in toluene, and after the addition of 1b,
the intermediate disappeared immediately. During further
investigations, a 15% desired product was obtained when the
stable phenylglyoxal monohydrate 1c directly reacted with 1b
(Scheme 4, eq 1). When 1b was added after 1c was heated for 2 h,
a 53% yield was achieved (Scheme 4, eq 2). In situ IR
Scheme 4. Control Experiments from Proposed Intermediates
C
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Letter
tautomerized into an enediol ligand 1i coordinating to
copper(II). After direct electron transfer, 1d and copper(I)
formed. The oxygen oxidized copper from (I) to (II) valence.
Stoichiometric control experiments (Scheme 3, eq 4 ahd 5)
indicated path A should be dominant. In addition, there was an
equilibrium between 1d and its monohydrate 1c in the system,
which was in favor of 1d. After 1b was added, alkynyl copper
formed. 1j would be generated by the addition of alkynyl copper
to phenylglyoxal. Subsequently, it was oxidized by copper(I)
thiophene-2-carboxylate and oxygen again to produce 1,4-
diphenylbut-3-yne-1,2-dione. Moreover, the dimer’s presence
in the mixture of intermediate was confirmed by X-ray
crystallography.14
With plenty of ynedione 1ab resulting from a gram-scale
reaction (Table 2, 1ab), further synthetic applications were
conducted to furnish various products including 3(2H)-
furanone, pyrazole, quinoxaline, and furanone in good-to-
excellent yields (Scheme 7). These diverse structures illustrate
the versatility of ynedione as synthetic building block.
DEDICATION
■
Dedicated to Professor Lixin Dai on the occasion of his 90th
birthday.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedure, NMR spectra, X-ray data (CIF), and
analytical data. This material is available free of charge via the
Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
■
Science 1996, 274, 2044.
(14) CCDC-1002199 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
*E-mail: xfjiang@chem.ecnu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by NSFC (21272075), NCET
(120178), DFMEC (20130076110023), the Fok Ying Tung
Education Foundation (141011), the Shanghai Pujiang Program
(12PJ1402500), the program for Professor of Special Appoint-
ment (Eastern Scholar) at Shanghai Institutions of Higher
Learning, and the program for the Changjiang Scholar and
Innovative Research Team in University.
D
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