A General Access to Propargylic Ethers through Br?nsted Acid Catalyzed Alkynylation of Acetals and Ketals with Trifluoroborates

Article abstract of DOI:10.1002/chem.201502797

A general Br?nsted acid catalyzed methodology for the alkynylation of acetals and ketals with alkynyltrifluoroborate salts has been developed. The reaction proceeds rapidly to afford valuable synthetic building block propargylic ethers in good to excellent yields. Unlike Lewis acid catalyzed transformations of trifluoroborates, this approach does not proceed via unstable organodifluoroborane intermediate. As a result, the developed methodology features excellent functional group tolerance and good atom economy. Br?nsted acid catalyzed alkynylation of acetals and ketals is described. Alkynyltrifluoroborate salts react rapidly to afford propargylic ethers. Organodifluoroborane, which is a common intermediate in Lewis acid catalyzed reactions of trifluoroborates, has not been observed. The reaction exhibits generally high yields and excellent functional group tolerance.

Full text of DOI:10.1002/chem.201502797

DOI: 10.1002/chem.201502797
Communication
&
Alkynylation
A General Access to Propargylic Ethers through Brønsted Acid
Catalyzed Alkynylation of Acetals and Ketals with
Trifluoroborates
Matthew Baxter and Yuri Bolshan*[a]
Abstract: A general Brønsted acid catalyzed methodology
for the alkynylation of acetals and ketals with alkynyl-
trifluoroborate salts has been developed. The reaction
proceeds rapidly to afford valuable synthetic building
block propargylic ethers in good to excellent yields.
Unlike Lewis acid catalyzed transformations of trifluoro-
borates, this approach does not proceed via unstable
organodifluoroborane intermediate. As
a result, the
developed methodology features excellent functional
group tolerance and good atom economy.
Propargylic ethers constitute an important class of organic
molecules.[1] Their amenability to rearrangements allows for
rapid access to a tremendous number of elaborate scaffolds. In
addition, they are known to possess biological activity.[2] Nucle-
ophilic,[3] electrophilic,[4] and metal-catalyzed[5] alkynylation
strategies have emerged as useful synthetic tools. The utility of
acetal alkynylation approach for the synthesis of propargylic
ethers has been demonstrated. In particular, reactions of acety-
lene nucleophiles including stannanes,[6] silanes,[7] alanes,[8]
gold,[9] copper,[10] and zinc[11] have been reported (Scheme 1).
Drawbacks of these methods include the necessity to use
excess amounts of Lewis acid catalysts, expensive metal com-
plexes, and low functional-group tolerance. Therefore, despite
their synthetic value, the efficient preparation of propargylic
ethers remains a challenge.
Scheme 1. Present methods and the developed protocol.
tions of trifluoroborates to stabilized carbocations such as
iminium[16] and, more recently, oxocarbenium ions[17] have
been reported. However, the challenges associated with Lewis
acid catalyzed approaches include the need to use excess
amounts of trifluoroborate salts and Lewis acids.
Furthermore, functional-group tolerance of these protocols
is low, due to the in situ generation of an unstable difluorobor-
ane intermediate. Though the reactions of allyl- and allenylpi-
nacolboronates are known,[18] Brønsted acid catalyzed reactions
of trifluoroborates are scarce. MacMillan and co-workers re-
ported conjugate addition of trifluoroborates to activated
enals in the presence of aqueous hydrofluoric acid.[19] The role
of hydrofluoric acid was to sequester boron trifluoride byprod-
uct. More recently, Aggarwal reported trifluoromethanesulfonic
acid catalyzed allylation-like addition of trifluoroborates to al-
dehydes.[20] In that case, however, a Brønsted acid promoted
the decomposition of trifluoroborates to difluoroboranes,
making this protocol mechanistically similar to Lewis acid
catalyzed reactions.
Here, we report a novel Brønsted acid catalyzed reaction of
trifluoroborate salts with acetals and ketals to afford propargyl-
ic ethers. Potassium organotrifluoroborate salts have emerged
as powerful shelf-stable equivalents of boronic acids in metal-
catalyzed processes.[12] Following a seminal contribution on the
Lewis acid catalyzed reaction of trifluoroborates by Matteson
and co-workers,[13] metal-free reactions of trifluoroborates
gained in popularity.[14,15] Current metal-free transformations of
trifluoroborate salts mainly rely on strong Lewis acids. Addi-
Taking into account the inherent nucleophilicity of trifluoro-
borates,[21] we envisaged that the activation of acetal using
a Brønsted acid will generate oxocarbenium ion without the
generation of organodifluoroborane intermediate. Therefore,
this approach would alleviate poor functional-group tolerance
and atom economy associated with Lewis acid catalysis. First,
a Brønsted acid screen was conducted using phenylacetalde-
[a] M. Baxter, Prof. Dr. Y. Bolshan
Faculty of Science
University of Ontario Institute of Technology (UOIT)
2000 Simcoe Street North, ON, L1H 7K4 (Canada)
Fax: (+1)905.721.3304
E-mail: yuri.bolshan@uoit.ca
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502797.
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Table 1. Optimization of Brønsted acid for the synthesis of 1a and 1b.
Entry
R
Brønsted acid
Temp [8C] Time [min] Yield[a] [%]
1
2
3
4
5
6
7[b]
PhCH2 HCl [4m] in dioxane 08C
60
60
60
60
15
15
15
34
36
28
86
89
60
83
PhCH2 HSbF6·6H2O
PhCH2 CF3COOH
PhCH2 HBF4·OEt2
PhCH2 HBF4·OEt2
08C
08C
08C
08C
Ph
Ph
HBF4·OEt2
HBF4·OEt2
08C
À108C
[a] Isolated material after column chromatography. [b] The reaction was
carried out at À108C.
hyde dimethyl acetal A1, and potassium phenylacetylene-
trifluoroborate (Table 1). Employment of HCl and HSbF6·6H2O
afforded 1a in a 34% and 36% yield respectively (Table 1,
entries 1 and 2), showing that a Brønsted acid could indeed
catalyze the addition. Trifluoroacetic acid was not effective as
a catalyst (entry 3). Upon using tetrafluoroboric acid diethyl
etherate, we were delighted to find that 1a was formed in an
86% yield (entry 4). A similar yield was observed when the
reaction time was reduced to 15 min (entry 5). Applying these
conditions to benzaldehyde dimethyl acetal A2 led to
a modest 60% yield of 1b (entry 6). Quick optimization
revealed that lowering the reaction temperature to À108C
improved the yield of 1b to 83% (entry 7).
Figure 1. Scope of the acetal substrates. [a] Reaction was stirred for 70 min.
[b] Reaction was carried out using 2.0 equiv of trifluoroborate, 1.5 equiv
HBF4·OEt2, and stirred for 80 min. All yields are isolated materials after
column chromatography.
Table 2. Optimization of conditions for electron-rich acetal.
In order to investigate the scope of the reaction, a library of
acetals was prepared[22] and coupled with phenylacetylene-
trifluoroborate (Figure 1). In general, benzaldehyde dimethyl
acetal derivatives afforded the desired products in good to ex-
cellent yields. Bromo- and chloro-substituted acetals afforded
products 1c and 1d in high yields of 89% and 80%, respec-
tively. Sterically hindered 2,6-dichlorobenzaldehyde dimethyl
acetal furnished product 1e in 64% yield. The reaction pro-
ceeded well in the presence of strong electron-withdrawing
groups. Both 4-nitro and 4-cyanobenzaldehyde dimethyl ace-
tals afforded propargylic ethers 1 f and 1g in excellent 99%
and 94% yields, respectively. Furthermore, the developed
methodology tolerated an unprotected carboxylic acid func-
tional group to produce product 1k in 73% yield. Cyclopentyl-
carboxaldehyde dimethyl acetal afforded propargylic ether 1g
in excellent yield. Hexenal dimethyl acetal afforded 1h in
a modest 49% yield.
Entry Temp [8C] Time [mins] Solvent
Yield 2a [%][a] Yield 2b [%][a]
1
2
3
4
5
À10
À30
À40
À40
À40
60
60
60
15
15
CH3CN
CH3CN
CH3CN
CH3CN
trace
66
21
0
70
0
62
0
CH3CH2CN 90
0
[a] Isolated material after column chromatography.
At À308C (Table 2, entry 2), 2a was formed in a 62% yield
and the byproduct 2b was no longer observed. Decreasing
temperature to À408C (Table 2, entries 3 and 4) resulted in
a slight increase of the yield. At this point, further temperature
reduction was not possible due to the melting point of
acetonitrile (À488C). As a result, we changed solvent to
propionitrile, which has a melting point of À938C. Interesting-
ly, a significant yield improvement from 62% to 90% has
been observed with propionitrile as a solvent, even at À408C
(entry 5).
Submitting electron-rich acetal A3 to the developed condi-
tions resulted in production of an overalkynylated product 2b
instead of the expected 2a (Table 2, entry 1). We hypothesize
that this is due to the inherent susceptibility of the product
to form a stabilized carbocation intermediate under acidic con-
ditions, which can further react with another equivalent of
the trifluoroborate salt. To suppress the formation of the unde-
sired byproduct 2b, we attempted to lower the reaction
temperature.
Next, we explored the scope of alkynyltrifluoroborate salts.
(Figure 2). Neutral biphenyl and naphthylacetylene trifluoro-
borate salts afforded propargylic ethers 3a, 3b, and 3c respec-
tively in high yields. Electron-rich p-butylphenylacetylene
trifluoroborate yielded 86% of 3d. Electron-deficient fluoro,
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Figure 3. Alkynylation of ketals.
9a (Table 3, entry 1). Increasing the amounts of trifluoroborate
salt and HBF4·OEt2 to 1.5 equiv increased the yield to 48%
(Table 3, entry 2). Further loading increase to 2.0 equiv
decreased the yield of 9a to 33% (entry 3). Decreasing the re-
action time to 15 min, changing the solvent to propionotrile,
and lowering the temperature to À408C marginally increased
the reaction yield (entries 4–6).
With these conditions in hand, the scope of the alkynylation
of ketals was explored (Figure 3). Modest yields were obtained
for entries 9b–9e. Substituents on ketals and trifluoroborate
salts did not seem to have a major impact on the yield.
Mechanistic studies of Lewis acid catalyzed addition of
trifluoroborates by Bode and co-workers[17] revealed that the
interaction of BF3·OEt2 and trifluoroborate resulted in the for-
mation of organodifluoroborane, which is a general drawback
of the Lewis acid catalyzed reactions of trifluoroborates. Due
to its poor stability and Lewis acidity, the range of chemical
moieties tolerated under Lewis acid catalysis is limited to alkyl,
ether, and halide functional groups. Additional experiments
have been conducted to gain insight into the mechanism of
this reaction. The addition of HBF4 to a solution of acetal and
phenylacetylenetrifluoroborate salt afforded propargylic ether
1b in 89% yield. In contrast, BF3·OEt2 did not promote the
reaction (Scheme 2), which eliminates the likelihood of Lewis
Figure 2. Scope of the trifluoroborate salts. [a] Reaction was conducted at
À408C.
chloro, and trifluoromethyl substituted derivatives of phenyl
acetylenetrifluoroborate salt reacted with various acetals to
produce products 3e–3i in good to excellent yields. Notably,
ketone, aldehyde, and ester functional groups were well
tolerated under the developed reaction conditions.
Next, we attempted to expand the reaction scope to ketals.
To our knowledge, the alkynylation of ketals has not been
reported in the literature. Our initial efforts to apply the devel-
oped protocol to ketals gave us 30% yield of propargylic ether
Table 3. Optimization of conditions for the alkynylation of ketals.
Scheme 2. The decomposition and reactivity pattern of trifluoroborate salt.
Entry
RBF3K/HBF4
[equiv]
Temp
[8C]
Solvent
Time
[min]
Yield[a] 9a [%]
acid catalysis. Furthermore, the combination of trifluoroborate
with tetrafluoroboric acid, followed by the addition of a sub-
strate, did not produce 1b. A similar outcome was observed
when acetal was added to a premixed solution of trifluoro-
borate and BF3·OEt2. 19F NMR in [D3]acetonitrile of RBF3K/HBF4
and RBF3K/BF3·OEt2 mixtures revealed a similar decomposition
pattern of trifluoroborate to difluoroborane. In the presence of
both HBF4 and BF3·OEt2 the peak associated with trifluoro-
1
2
3
4
5
6
1.1/1.1
1.5/1.5
2.0/2.0
1.5/1.5
1.5/1.5
1.5/1.5
À10
À10
À10
À10
À10
À40
CH3CN
CH3CN
CH3CN
CH3CN
CH3CH2CN
CH3CH2CN
70
70
70
15
15
15
30
48
33
50
52
53
[a] Isolated material after column chromatography.
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Communication
borate salt at 134.6 ppm disappeared, giving rise to a peak at
150.7 ppm. Due to the fact that the addition of acetal to both
mixtures did not yield the product 1b, we conclude that the
developed reaction does not proceed via the generation of
organodifluoroborane intermediate. Therefore, the proposed
mechanism of this Brønsted acid promoted transformation
includes direct addition of nucleophilic trifluoroborate salts to
oxocarbenium ions. Another piece of evidence in support of
an alternative mechanism is the tolerance of a variety of
functional groups, which is not observed in the reactions
where organodifluoroborane intermediate is present.
Keywords: alkynylation · borates · Brønsted acids · propargylic
ethers
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reaction was stirred for 15 min at À108C.
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Alkynylation of ketals
To trifluoroborate salt (0.15 mmol, 1.5 equiv), in acetonitrile
(1.0 mL) ketal (0.10 mmol, 1.0 equiv) was added under argon and
the solution was allowed to stir at À408C for two minutes. Subse-
quently, HBF4·OEt2 (0.15 mmol, 1.5 equiv) was added and the reac-
tion was stirred for 15 min at À408C. The reactions after both
methods were diluted with ethyl acetate (25 mL). The organic layer
was washed with water (2”10 mL), brine (1”10 mL), dried over
MgSO4, filtered, and concentrated in vacuo. The crude product was
purified by flash column chromatography using hexanes/diethyl
ether.
Acknowledgements
This work was supported by the Natural Sciences and Engi-
neering Research Council of Canada (NSERC). M.B. thanks Ms.
Kayla Fisher (UOIT) for her assistance in the laboratory.
Received: July 16, 2015
Published online on August 6, 2015
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