Oxidative Coupling of Terminal Alkynes with Aldehydes Leading to Alkynyl Ketones by Using Indium(III) Bromide

Article abstract of DOI:10.1002/chem.201504255

An indium(III)-promoted direct acylation of terminal alkynes using aldehydes leading to ynones was developed. In contrast to the previous addition reactions of alkynes to aldehydes, which provide propargylic alcohols, the oxidative coupling proceeded exclusively to afford alkynyl ketones. The products were likely generated through an Oppenauer oxidation of the indium propargylic alkoxide species by excess amounts of aldehydes.

Full text of DOI:10.1002/chem.201504255

DOI: 10.1002/chem.201504255
Communication
&
Acylation
Oxidative Coupling of Terminal Alkynes with Aldehydes Leading
to Alkynyl Ketones by Using Indium(III) Bromide
Yohei Ogiwara, Masahito Kubota, Kotaro Kurogi, Takeo Konakahara, and Norio Sakai*[a]
Abstract: An indium(III)-promoted direct acylation of ter-
minal alkynes using aldehydes leading to ynones was de-
veloped. In contrast to the previous addition reactions of
alkynes to aldehydes, which provide propargylic alcohols,
the oxidative coupling proceeded exclusively to afford al-
kynyl ketones. The products were likely generated
through an Oppenauer oxidation of the indium propargyl-
ic alkoxide species by excess amounts of aldehydes.
Carbon–carbon bond formation using organoindium reagents
is an important and powerful strategy in organic synthetic
chemistry, because these reagents exhibit a high tolerance
toward various functional groups that are sensitive to strong
Scheme 1. Pathways for a) propargylic alcohols and b) alkynyl ketones.
basic conditions in comparison with other nucleophilic organo-
metallics such as organolithium, organomagnesium, and orga-
nozinc reagents.[1] In 2003, our group reported the InBr3-pro-
Acylation of terminal alkynes is one of the most important
moted nucleophilic addition of a terminal alkyne to an alde-
hyde in the presence of Et3N, which produced propargylic alco-
hol.[2] In this reaction, the alkynyl indium was formed in situ
from a terminal alkyne and InBr3 with an amine base; it acted
as a metal nucleophile to attack the aldehyde, forming indium
alkoxide A. The subsequent protonation by an aqueous
workup led to the final propargylic alcohol (Scheme 1a). This
method successfully utilized a variety of either alkynes or alde-
hydes due to the fact that the indium(III) compound has
a mild basicity and a strong functional group tolerance. In con-
trast, when excess aldehyde was applied to the present
system, the formation of both an alkynyl ketone and a benzyl
alcohol was confirmed.[3] The formation of these two products,
(the alkynyl ketone and the benzyl alcohol), suggested that
Oppenauer oxidation[4] occurred during the reaction; the hy-
dride was transferred from the a-carbon of the indium alkox-
ide A to excess amounts of the aldehyde (Scheme 1b).[5,6] This
led us to believe that a direct preparation of alkynyl ketones
from alkynes and aldehydes could be achieved by an indium-
promoted one-pot addition/oxidation strategy.
approaches to alkynyl ketones, which function as valuable
building blocks in organic and pharmaceutical chemistry. In
many cases, however, the acylation reagents are limited to acyl
halides, or aryl halides under carbon monoxide through either
Sonogashira-type or carbonylative coupling.[7,8] An oxidative
acylation of terminal alkynes using aldehydes is shown in
Scheme 1b and is considered to be a novel and more straight-
forward procedure to access this class of structures. Although
a similar ZnI2-mediated transformation of an alkyne with an al-
dehyde has recently been reported, the conversion was limited
to only one example, a combination of phenylacetylene with
benzaldehyde.[9] Despite its high synthetic potential utility, the
investigation into the generality of terminal alkynes and alde-
hydes in the present reaction remains unexplored. In this com-
munication, we describe a novel approach to the production
of alkynyl ketones using an indium(III)-mediated direct cou-
pling of terminal alkynes and aldehydes through Oppenauer
oxidation.
On the basis of our previous results,[2,3] optimization of the
reaction conditions for the oxidative coupling of phenylacet-
ylene (1) with 4-methylbenzaldehyde (2) was initially examined
(Table 1). When the reactions of 1 with 3 equiv of 2 were con-
ducted in the presence of 1 equiv each of several indium(III)
salts and Et3N in 3m of Et2O at room temperature for 24 h
(Table 1, entries 1–6), InBr3 was effective, and the desired
ynone 3 was obtained in a 65% GC yield (entry 2). The use of
1.5 equiv each of InBr3 and Et3N led to an increase in the yield
to 76% (entry 7). The high concentration of substrates was
a critical factor in achieving the desired transformation. Practi-
[a] Dr. Y. Ogiwara, M. Kubota, K. Kurogi, Dr. T. Konakahara, Prof. Dr. N. Sakai
Department of Pure and Applied Chemistry
Faculty of Science and Technology
Tokyo University of Science
2641 Yamazaki, Noda, Chiba 278-8510 (Japan)
E-mail: sakachem@rs.noda.tus.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201504255.
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Communication
Table 1. Optimization for oxidative coupling of 1 with 2.[a]
Entry
InX3
Et2O [M]
Temp. [8C]
Yield of 3 [%][b]
1
2
3
4
5
InCl3
InBr3
InI3
In(OH)3
In(OAc)3
In(OTf)3
InBr3
InBr3
InBr3
3
3
3
3
3
3
3
2
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
40
25
65
40
0
0
0
76
68
6
7[c]
8[c]
9[c]
10[c]
11[c]
1
0.2
3
57
32
83[d] (80)
InBr3
InBr3
[a] Reaction conditions: 1 (0.6 mmol), 2 (1.2 mmol), InX3 (0.6 mmol), Et3N
(0.6 mmol), 24 h. [b] GC yield (isolated yield). [c] Used 1.5 equiv each of
InBr3 (0.9 mmol) and Et3N (0.9 mmol). [d] The corresponding benzyl alco-
hol, 4-methylbenzyl alcohol, was obtained in an 82% GC yield (based on
1).
cally, when the initial concentration of 1 was decreased from 3
to 0.2m, the yield of 3 was lower (entries 7–10). Finally, elevat-
ing the reaction temperature to 408C improved the yield of
product 3 to an 83% GC yield, the product of which was iso-
lated in an 80% yield with the formation of a benzyl alcohol,
4-methylbenzyl alcohol, was derived from aldehyde 2 in an
82% GC yield (based on alkyne 1).
The generality of both terminal alkynes and aldehydes for
this coupling was next investigated and the isolated yields of
the alkynyl ketones are summarized in Scheme 2. The coupling
of phenylacetylene with benzaldehyde or a variety of its deriv-
atives can be applied to this transformation to form the corre-
sponding alkynyl ketones. Benzaldehydes with electron-donat-
ing methoxy and methyl groups at their 4- and 3-positions af-
forded 4 and 5 in good yields, respectively. With the use of the
more sterically-hindered 2-methylbenzaldehyde, however, the
yield of 6 was slightly decreased to 32%. The reactions of both
benzaldehyde and a bromo-substituted variation at the 4-posi-
tion proceeded smoothly to form 7 and 8. In the cases of
chlorobenzaldehydes as a substrate, a similar steric effect was
observed as well as cases of methylbenzaldehydes, in particu-
lar, and chloro-substituted aldehydes at the 4- and 3-positions
were slightly more reactive than those aldehydes bearing
chlorine at the 2-position, affording 9, 10, and 11, in 81, 83,
and 58% yields, respectively. The electron-poor substrates,
such as 4-cyano-, and 4-nitro benzaldehyde, are applicable to
this transformation to form the corresponding alkynyl ketones
12 and 13. Also, the aldehyde with a heteroaromatic ring was
converted into 14 in a 69% yield. The reaction with a linear ali-
phatic aldehyde, pentanal, gave no cross-coupled product,
probably due to the aldol-type side reaction, but the reaction
of pivalaldehyde, which has no a-hydrogen, with alkyne 1 af-
forded the expected ynone 15 in a practical yield. Several aryl-
Scheme 2. InBr3-mediated oxidative coupling of terminal alkynes with alde-
hydes. Reaction conditions: alkyne (0.6 mmol), aldehyde (1.8 mmol), InBr3
(0.9 mmol), Et3N (0.9 mmol), Et2O (0.2 mL), 408C, 24 h. [a] NMR yield in the
crude mixture. [b] Net yields after a silica gel column chromatography: 22
was isolated in a 40% isolated yield, the remaining 20% of 22 was obtained
as a mixture of 10% of 22’.
and alkylacetylenes were also coupled with benzaldehyde
under these reaction conditions to form ynones. For example,
arylacetylenes bearing electron-donating groups, such as 4-me-
thoxy, 4-methyl, and 2-methyl groups, reacted with benzalde-
hyde successfully to isolate the products 16–18 in good yields.
When the reaction of the electron-withdrawing chloro- and
nitro-substituted arylacetylenes was conducted with benzalde-
hyde, the corresponding products 19 and 20 were obtained in
83 and 76% yields, respectively. This method could be applica-
ble to an alkylacetylene, 3,3-dimethyl-1-butyne, producing tert-
butyl-substituted ynone 21. Although, the oxidative coupling
of trimethylsilylacetylene with benzaldehyde provided TMS-
substituted enone 22 as a sole product, the desilylation partly
occurred at the purification step by a silica gel column chro-
matography to give unsubstituted ethynyl ketone 22’.
Next, we conducted a deuterium-labeling experiment as
a preliminary mechanistic study to estimate the quantitation of
Chem. Eur. J. 2015, 21, 18598 – 18600
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Communication
tion, Culture, Sports, Science and Technology (MEXT) and by
the Sasakawa Scientific Research Grant from The Japan Science
Society.
Keywords: acylation · alkynes · CÀC coupling reaction ·
hydrogen transfer · indium
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Scheme 3. Deuterium-labeling experiment.
deuterium content in the product and observe the formation
of the propargylic alcohol as an intermediate (Scheme 3).
When the reaction of phenylacetylene 1 with 3 equiv of deu-
terated benzaldehyde [D1]23 was carried out with InBr3 and
Et3N (1 equiv each) at a lower reaction temperature for 24 h,
the formation of both a 61% yield of the oxidative coupling
product 7 and a 60% yield of the corresponding benzyl alco-
hol [D2]24 with a high deuterium incorporation (>99%) at the
benzylic carbon was observed after the usual aqueous workup.
Also, the propargylic alcohol [D1]25 containing a deuterium
atom at the propargylic position was simultaneously detected
as a byproduct. The results supported our working hypotheses
(Scheme 1): 1) the nucleophilic addition of a terminal alkyne to
an aldehyde produced a propargylic alcohol and 2) Oppenauer
oxidation by an aldehyde formed an alkynyl ketone and
a benzyl alcohol.
In summary, we have developed an InBr3-promoted oxida-
tive coupling of terminal alkynes with aldehydes to access
ynones. A variety of aromatic- and heteroaromatic aldehydes,
and alkyl varieties were acceptable for this coupling. Several
terminal alkynes also can be used as nucleophiles without
a strong base. On the basis of our previous results and a pre-
liminary mechanistic experiment, this straightforward method
proceeds through nucleophilic addition and Oppenauer oxida-
tion mediated by the indium complex. This addition/oxidation
strategy would be potentially applicable for many other trans-
formations. The catalytic applications of indium(III)[10,11] and
other indium nucleophile versions of this reaction are now in
progress.
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[11] The catalytic application of InBr3 was also investigated for this transfor-
mation, but the ynone 3 was not generated more than the catalytic
amount.
Acknowledgements
This work was partially supported by a Grant-in-Aid for Scien-
tific Research (C) (No. 25410120) from the Ministry of Educa-
Received: October 22, 2015
Published online on November 5, 2015
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www.chemeurj.org
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