Metal-free synthesis of ynones from acyl chlorides and potassium alkynyltrifluoroborate salts

Article abstract of DOI:10.1021/ol403370t

A straightforward method for the preparation of ynones from acyl chlorides and potassium alkynyltrifluoroborate salts has been developed. The one-pot reaction proceeds rapidly in the presence of a Lewis acid without exclusion of air and moisture.

Full text of DOI:10.1021/ol403370t

Letter
pubs.acs.org/OrgLett
Metal-Free Synthesis of Ynones from Acyl Chlorides and Potassium
Alkynyltrifluoroborate Salts
Cassandra Taylor and Yuri Bolshan*
University of Ontario Institute of Technology (UOIT) 2000 Simcoe Street North, Oshawa, Ontario, Canada L1H 7K4
S
* Supporting Information
ABSTRACT: A straightforward method for the preparation of ynones from acyl chlorides and potassium alkynyltrifluoroborate
salts has been developed. The one-pot reaction proceeds rapidly in the presence of a Lewis acid without exclusion of air and
moisture.
nones are important building blocks in organic chemistry
nonmetal-catalyzed reactions.17 However, the field of tran-
Ythat have been shown to have biomedical and material sition-metal-free reactions of trifluoroborates is still in its
significance.1 In addition, they are precursors to valuable
infancy stage.
organic functional groups such as pyrimidines,2 quinolones,3
Our initial efforts were focused around the preparation of
ynone 1a from phenylacetylenetrifluoroborate S1 and benzoyl
chloride. Several Lewis acids were screened in an effort to find
an effective catalyst (Table 1). First, Lewis acids known to react
furans,4 pyrazoles,5 flavones,6 oximes,7 and chiral propargylic
alcohols.8 A common route to prepare ynones involves the
reaction of metal9 and metalloid10 acetylides with acid
chlorides. Alternatively, the synthesis of ynones from acyl
Table 1. Optimization of Conditions for the Preparation of
Ynone 1a
chlorides can be achieved via two-step procedures using
Weinreb amides and organolithium or Grignard reagents.11
Another common approach includes the addition of organo-
lithium or Grignard reagents to an aldehyde, which is followed
by the oxidation of a secondary alcohol to the corresponding
ketone.12 The necessity of purifying synthetic intermediates
after each step and poor functional group tolerance of metal
acetylides are main deficiencies of the aforementioned methods.
Therefore, the utility of ynones as synthetic building blocks
highlights the attractiveness of a more straightforward method.
More recently, transition-metal-catalyzed carbonylative cou-
plings for the preparation of ynones have emerged as an
alternative approach.13 However, in addition to cost and
toxicity associated with transition metals, metal-catalyzed
carbonylative reactions often require elevated CO pressures
and suffer from the presence of an undesired Sonogashira
coupling byproduct.
Our research program is focused on the investigation of
transition-metal-free reactions of organoboranes. Therefore, we
sought to develop a novel method for the preparation of
ynones from acyl chlorides and alkynyltrifluoroborate salts.
Potassium organotrifluoroborate salts have recently emerged as
versatile reagents in organic synthesis. Their ease of
preparation, inherent stability, functional group tolerance, and
low toxicity have made trifluoroborates attractive reagents.14
Organotrifluoroborate salts have long been considered a bench-
stable equivalent of boronic acids for palladium-catalyzed
Suzuki−Miyaura coupling.15 Following a seminal work by
Matteson and co-workers,16 Bode, Molander, and others have
highlighted the utility of organotrifluorborates as reagents in
a
entry
Lewis acid
Lewis acid (equiv)
conditions
yield (%)
b
1
SiO2
16.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
1.0
2.0
1.0
1.5
1.0
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
0
2
3
SiCl4
trace
trace
24
BF3·OEt2
FeCl3
AlCl3
b
4
c
5
62
d
6
AlCl3
66
e
7
AlCl3
60
8
AlCl3
trace
trace
33
9
AlCl3
toluene
ClCH2CH2Cl
DMSO
10
11
12
13
AlCl3
AlCl3
trace
trace
0
AlCl3
acetonitrile
CH2Cl2
CH2Cl2
CH2Cl2
AlCl3·6H2O
BCl3
b
14
67
15
BBr3
20
a
Reactions were run with 1 equiv of benzoyl chloride and 1 equiv of
b
potassium phenylacetylenetrifluoroborate S1. 1.5 equiv of S1.
c
d
Anhydrous conditions. The reaction was done in nondried glassware
e
under air. Anhydrous conditions + 1 μL of water.
Received: November 20, 2013
© XXXX American Chemical Society
A
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Organic Letters
Letter
with trifluoroborate salts have been explored. Silica gel,18 silicon
tetrachloride,15 and boron trifluoride17c,e have been reported to
convert organotrifluoroborates to organodihaloboranes. Un-
fortunately, their addition did not promote the formation of the
desired ynone (Table 1, entries 1−3). Product 1a was obtained
in low yield when an iron(III) chloride catalyst was employed
(Table 1, entry 4). Next, aluminum(III) chloride was
investigated due to its well-established ability to promote
oxocarbenium ion formation in Friedel−Crafts acylations.19 We
were pleased to obtain the desired product in 62% yield for the
AlCl3-catalyzed reaction (Table 1, entry 5).
A slightly elevated yield was obtained when the reaction was
performed in the presence of air with glassware that was not
dried beforehand (Table 1, entry 6). The addition of a
controlled amount of water to the reaction mixture did not
improve the yield (Table 1, entry 7). Once it became evident
that the reaction could tolerate air and moisture, subsequent
reactions (Table 1, entries 8−15) were done in nondried
glassware under air. Further attempts to optimize the solvent
revealed that dichloromethane (CH2Cl2) is particularly well
suited to the reaction. Aprotic solvents including THF, toluene,
and dichloroethane as well as polar solvents DMSO and
acetonitrile were tested with little success (Table 1, entries 8−
12).
Unfortunately, inconsistencies in the results of the aluminum
chloride-catalyzed reactions prompted us to explore alternative
catalysts. We hypothesized that the formation of AlCl3 hydrate
inhibited the reaction. Indeed, commercially available
aluminum(III) chloride hexahydrate was completely inactive
under the reaction conditions (Table 1, entry 13). To our
delight, boron trichloride was found to produce similar yields
with better consistency (Table 1, entry 14).
The scope of the reaction has been explored using
phenylacetylenetrifluoroborate salt S1 and a variety of acyl
chlorides (Figure 1). Unsubstituted naphthyl and biphenyl acyl
chlorides afforded the expected products in synthetically useful
yields (1b,c). Benzoyl chloride derivatives bearing electron-
donating substituents furnished the corresponding ynones in
excellent yields (1d−g). In contrast, electron-withdrawing
substituents resulted in comparatively modest yields (1h,i,m).
The reaction was not sensitive to steric effects. High yields were
observed for both para- and ortho-substituted benzoyl chloride
derivatives (1f,g). Moreover, the reaction of o-chlorobenzoyl
chloride resulted in 59% yield, which is a significant yield
increase when compared to p-chlorobenzoyl chloride (1h,i).
We hypothesize that the steric interaction of the substituent in
the ortho position forces the carbonyl functional group out of
the plane, offsetting the electron-withdrawing character of the
aromatic ring. The expected ynones were obtained in good
yields for both cyclohexyl and cyclopropyl carbonyl chlorides as
well as acetyl chloride (1j−l). Notably, 4-bromobutyryl
chloride reacted under the developed reaction conditions to
afford the desired product 1m in 39% yield. To our knowledge,
this is the first protocol for the synthesis of ynones to tolerate
an alkyl bromide functional group.
Figure 1. Reactions of phenylacetylenetrifluoroborate salt S1 with acyl
chlorides. Reactions were run with 1 equiv of acyl chloride, 1.5 equiv
of potassium phenylacetylenetrifluoroborate S1, and 1.5 equiv of
boron trichloride.
proved to be less reactive substrates. Modest yields were
obtained when hexynyl- and cyclopentylethynyltrifluoroborate
salts were reacted with electron-rich benzoyl chloride
derivatives (4a, 5a).
On the basis of these experiments, three plausible
mechanistic pathways are proposed (Scheme 1). Upon
interaction of the potassium alkynyltrifluoroborate with BCl3,
an organodichloroborane species is formed.20 Coordination of
the electrophilic organodichloroborane with the acyl chloride
leads to the formation of a nucleophilic borate and an activated
carbonyl functional group. Subsequent transfer of an alkynyl
moiety leads to the formation of a tetrahedral intermediate,
which collapses to form the desired product (path A).21
Alternatively, coordination of the organodichloroborane species
could be followed by an intramolecular chloride transfer. The
generated oxocarbenium ion may combine with the organo-
borate to afford the desired ynone (path B). Finally, the
organodichloroborane intermediate may act as a Lewis acid and
react directly with the acyl chloride in a mechanism analogous
We further evaluated the scope of the reaction by preparing
several other examples of potassium alkynyltrifluoroborate salts
to examine their reactivity under the developed conditions
(Figure 2). In general, derivatives of the phenylacetylenetri-
fluoroborate salt bearing electron-donating substituents on the
aromatic ring reacted with both aromatic and aliphatic acyl
chlorides to produce ynones in good to excellent yields (2a−c,
3a−c). Aliphatic derivatives of the alkynyltrifluoroborate salts
B
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Letter
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization data for organo-
trifluoroborate salts and compounds 1a−m, 2a−c, 3a−c, 4a,
and 5a. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: yuri.bolshan@uoit.ca.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the UOIT start-up fund. We thank
Mr. Matthew Baxter (UOIT) for his assistance in the
laboratory.
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