Calcium-catalyzed carboarylation of alkynes

Article abstract of DOI:10.1002/chem.201406503

The first transition-metal-free carboarylation of alkynes with commercial and readily available alcohols as alkylating agents was realized in the presence of an environmentally benign calcium catalyst. Thereby, a novel protocol for the one-step synthesis of highly congested, all-carbon tetrasubstituted alkenes, as incorporated in potentially bioactive, complex dihydronaphthalene, chromene and dihydroquinoline structures, is provided. The reaction features an unprecedented, particularly wide substrate scope, good functional-group tolerance and simple experimental operation under mild reaction conditions. Finally free: The first transition-metal-free one-step synthesis of highly congested, all-carbon tetrasubstituted olefins has been realized by a calcium-catalyzed carboarylation reaction. Internal alkynes react with alcohols as alkylating reagent under mild reaction conditions, which provides access to a variety of useful structural scaffolds via highly reactive trisubstituted vinyl cations.

Full text of DOI:10.1002/chem.201406503

DOI: 10.1002/chem.201406503
Communication
&
Carboarylation |Hot Paper|
Calcium-Catalyzed Carboarylation of Alkynes
Liang Fu and Meike Niggemann*[a]
Abstract: The first transition-metal-free carboarylation of
alkynes with commercial and readily available alcohols as
alkylating agents was realized in the presence of an envi-
ronmentally benign calcium catalyst. Thereby, a novel pro-
tocol for the one-step synthesis of highly congested, all-
carbon tetrasubstituted alkenes, as incorporated in poten-
tially bioactive, complex dihydronaphthalene, chromene
and dihydroquinoline structures, is provided. The reaction
features an unprecedented, particularly wide substrate
Scheme 1. Carbon electrophile-triggered carboarylation of internal alkynes.
scope, good functional-group tolerance and simple experi-
mental operation under mild reaction conditions.
second, being a carbon nucleophile (Scheme 1). Thereby, the
need to proceed via a vinyl–metal intermediate is avoided
from the outset. The feasibility of this approach was demon-
strated recently with the development of a copper-catalyzed
carboarylation of alkynes, in which the copper catalyst is used
for the generation of aromatic electophiles from a diaryliodoni-
um salt.[5] In addition, iron salts have been shown to catalyze
the annulation of benzylic alcohols with alkynes for the forma-
tion of indenes.[8] Nevertheless, both of these methods are lim-
ited in scope as only aryl and benzyl cations are known to
induce this highly valuable transformation, and transitions
metal catalysts are still needed.
All-carbon tetrasubstituted olefins are frequently found in nat-
ural products, pharmaceuticals, and materials and represent
versatile starting materials for the synthesis of complex fine
chemicals.[1] However, the congested nature of these olefins
encumbers their synthesis through classical procedures such as
carbonyl olefination or olefin metathesis.[1a] Although several
methods have been developed to access them from alkynes in
a stepwise fashion,[1a,2] catalytic protocols for the one step as-
sembly of these densely substituted building blocks remain
a challenge to synthetic organic chemists. This is undoubtedly
due to the fact that most procedures for the introduction of
substituents to alkynes proceed via a carbometallation step,
followed by further elaboration of the resulting vinyl–metal
species A (Scheme 1). In catalytic one-step protocols this elab-
oration is often just a simple protodemetallation, consequently
limiting the scope of accessible olefins to trisubstituted ones.
In addition, air and moisture sensitive stoichiometric metal-or-
ganic reagents and transition-metal catalysts such as nickel,[3]
palladium,[4] copper[5] or iron salts[6] are mandatory.
Calcium is one of the five most abundant elements in the
earth’s crust and it is therefore inexpensive and non-toxic even
in substantial amounts. Over the last couple of years, our
group has focused on developing an environmentally friendly
calcium catalyst to replace expensive and highly toxic noble
metal catalysts in synthetic chemistry.[9] We have successfully
utilized simple calcium salts as a highly efficient Lewis acid cat-
alysts for the transformation of readily available alcohols into
a broad variety of reactive carbocations.
The active Lewis-acidic calcium catalyst CaNTf2PF6, required
for the ionizing deoxygenation of the alcohol, is formed in situ
by anion exchange upon the combination of Ca(NTf2)2 and
Bu4NPF6. Its particularly high reactivity originates presumably in
a double role of the calcium catalyst. It activates the CÀO
bond for bond cleavage by withdrawing electron density via
coordination to the hydroxy oxygen. At the same time a tem-
porary leaving group, “NTf2CaOH”, is installed, due to the par-
ticular stability of CaÀO bonds.
An ideal strategy towards all-carbon tetrasubstituted olefins
engages the activation of the CꢀC triple bond for the subse-
quent introduction of a carbon nucleophile by an electrophilic
carbon reagent, such as a carbocation, in analogy to the classi-
cal acid catalyzed hydroarylation of alkynes.[7] In other words,
the two carbon substituents are introduced concomitantly. The
first one as an electrophile that generates an intermediary,
highly reactive vinyl cation B, which is then trapped by the
Based on these hypotheses, we examined the reaction of
acetylene 1a with 4-hydroxyphenylethanol 2a as model sub-
strates, in the presence of 5 mol% Ca(NTf2)2 and 5 mol%
Bu4NPF6. To our delight, the reaction indeed occurred, and
gave the isolated carboarylation adduct 3a in 56% yield after
12 h reaction time (Table 1, entry 1). Inspired by this result, we
started further optimization of the reaction conditions. Sol-
[a] L. Fu, Prof. Dr. M. Niggemann
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
E-mail: niggemann@oc.rwth-aachen.de
Homepage: http://www.ioc.rwth-aachen.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406503.
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vents had significant influence on the formation of 2a and the
yield was improved by using CH3NO2 instead of dichoroethene
(DCE; Table 1, entry 2). We also found alternative organic salts,
such as NH4PF6 and Bu4NSbF6, to be equally efficient as cocata-
lysts (Table 1, entries 3 and 4). Notably, decreasing the additive
loading to 2.5 mol% improved the yield of the reaction
(Table 1, entry 5).
Table 2. Substrate scope: Carbon electrophiles from alcohols.
Table 1. Optimization of the carboarylation of 1a with 2a.
Entry[a]
Additive (mol%)
Solvent
Yield [%][b]
1
2
3
4
5
6
7[c]
8
Bu4NPF6 (5)
Bu4NPF6 (5)
NH4PF6 (5)
Bu4NSbF6 (5)
Bu4NPF6 (2.5)
Bu4NPF6 (2.5)
Bu4NPF6 (2.5)
–
DCE
56
83
80
81
85
77
82
–
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2/DCE (1:1)
CH3NO2
[a] Bu4NPF6 and Ca(NTf2)2 were added to 1a (0.48 mmol) and
2
CH3NO2
CH3NO2
CH3NO2
(0.4 mmol) in CH3NO2 (2 mL) and stirred at 408C for 12 h; [b] yield of iso-
lated product; [c] 2 mL DCE/CH3NO2 (1:1) were used. [d] 2 mL DCE was
used.
9[d]
10[d]
Bu4NPF6 (2.5)
–
70
71
[a] Additive and Ca(NTf2)2 were added to 1a (0.48 mmol) and 2a
(0.4 mmol) in solvent (2 mL) and stirred at 408C for 12 h; [b] yield of iso-
lated product; [c] 2 equivalents of 2a were used; [d] HNTf2 (10 mol%)
was used.
(Table 2, 3i–k). Finally, the substrate scope was successfully ex-
tended to allylic alcohols (Table 2, 3l and 3m).
Secondly, we varied the substituents on the CꢀC triple
bond. Both aryl and heteroaryl groups gave the desired ad-
ducts in excellent yields (Table 3, 3n–q). As an alternative, yn-
amides could also be used, thus providing access to more
complex dihydronaphthalene derivatives (Table 3, 3r). Once
more showcasing the robustness of the presented method to-
wards steric hindrance, it is noteworthy that the preparation of
axial chiral compounds using 2-anisyl and 1-naphthyl groups
(Table 3, 3o and 3p) was highly efficient, albeit yielding race-
mic mixtures under the current reaction conditions.
Mixed solvents and two equivalents of alcohol 2a were also
examined, but no better results were obtained (Table 1, en-
tries 6 and 7). The absence of Bu4NPF6 resulted in no conver-
sion (Table 1, entry 8). HNTf2 (10 mol%) was identified to be
a less efficient catalyst for the reaction (Table 1, entries 9 and
10). The superior levels of reaction efficiency with 5 mol%
Ca(NTf2)2 and 2.5 mol%Bu4NPF6 in CH3NO2 at 408C for 12 h
(Table 1, entry 5) were selected for further exploration.
We first examined the scope of the reaction towards a variety
of readily available alcohols (Table 2). We found that electron-
donating and -withdrawing groups, as well as reactive groups
on the aromatic ring, such as OH, OCH3, CH3, or Cl at C4 posi-
tions and NHTs at C2 position, were well tolerated (Table 2,
3a–f). Some alcohols, such as 2b–m gave poor conversions in
CH3NO2 as a reaction medium. The reactivity was found to be
restored in DCE, albeit at the expense of product selectivity, as
significant amounts of dihydronaphthalene 5 resulting from
a direct hydroarylation of the alkyne (cf. discussion of the
mechanism; see below) were formed alongside the desired
carboarylation product 3. We were pleased to find that
a mixed solvent system (DCE/CH3NO2 1:1) allowed for a suffi-
cient reactivity of the alcohol and at the same time suppressed
the formation of the undesired hydroarylation product 5. Nota-
bly, even sterically hindered alcohols reacted smoothly in ex-
cellent yields (Table 2, 3g and 3h). In addition, not only alkenyl
but also alkynyl groups were well tolerated by the reaction
Next, we examined the linking unit between the aryl nucleo-
phile and the CꢀC triple bond. Apart from the ethylene link-
age, oxygen and nitrogen substituents proved to readily yield
chromene and dihydroquinoline derivatives (Table 3, 4a and
4b). The dihydroquinoline derivatives were obtained without
chromatographic purification in 73% yield by simple filtration
after reaction completion. The additional steric bulk of a sub-
stituent in the linking unit was again well tolerated (Table 3,
4c). As typical for intermolecular carbocation additions,[10] the
diastereoselectivity was found to be mediocre, which might be
attributed to the slenderness of the alkyne nucleophile. More
importantly, seven-membered rings could be formed, due to
the high reactivity of the vinyl cation, which further broadens
the substrate scope (Table 3, 4d).
Finally, we focused on our studies on the scope of nucleo-
philic arenes (Table 4). The reaction was very general with re-
spect to the electronic properties of the substituent on the
ring of nucleophilic arenes (Table 4, 3s–v). Most notably, the
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The mechanism of the calcium-catalyzed carboarylation can,
in principle, proceed via two different pathways (Scheme 2,
paths a and b). In the first, the calcium catalyst initially gener-
ates a carbocation A from the alcohol 2 that attacks the func-
tionalized alkyne 1. Thereupon, a trisubstituted highly reactive
vinyl cation B is formed, which is attacked by the tethered aryl
Table 3. Substrate scope: Alkyne substituent and linking unit.
Scheme 2. Proposed mechanisms for the carbon electrophile-triggered car-
boarylation of internal alkynes with alcohols by calcium catalysis.
[a] Additive and Ca(NTf2)2 were added to
1 (0.48 mmol) and 2a
(0.4 mmol) in CH3NO2 (2 mL) and stirred at 408C for 12 h; [b] yield of iso-
lated product; [c] reaction at 808C for 12 h; d.r. determined by 1H NMR
spectroscopy of the crude mixture.
nucleophile (ArH, path a). An alternative process (path b) is ini-
tiated by the activation of the alkyne by the Lewis-acidic calci-
um catalyst, resulting in the formation of a Lewis acid-bound
vinyl cation and immediate protodemetallation with adventi-
tious water, in analogy to the previously described activation
of alkenes.[11] The disubstituted vinyl cation C then reacts with
the tethered aryl nucleophile (ArH), yielding a direct hydroar-
ylation product 5. Product formation then occurs via a subse-
quent Friedel–Crafts type addition of the cation A that is once
again generated from the alcohol 2 by the calcium catalyst. To
gain insight into which of the two pathways is operative, espe-
cially due to the aforementioned fact that in some reactions 5
was formed as a byproduct, 5 was reacted with alcohols under
the standard reaction conditions. The desired products 3a and
3b were obtained in 8% and 21% yield alongside unreacted
dihydronaphthalene 5 (Scheme 3). These results clearly support
the first, direct reaction pathway (Scheme 2, path a).
Table 4. Substrate scope: Arene nucleophiles.
In conclusion, we have developed an alkyne carboarylation
process that provides a concise route for the one-step prepara-
tion of all-carbon tetrasubstituted olefins in the presence of an
environmentally benign calcium catalyst, using commercial
and readily available alcohols as alkylation reagents. The reac-
tion proceeds via a highly reactive trisubstituted vinyl cation
and therefore allows for the use of deactivated, fluorine-substi-
tuted arenes as tethered nucleophiles and tolerates a great
deal of steric congestion. In addition, the preparation of poten-
tially bioactive chromene and dihydroquinoline derivatives
makes this procedure particularly useful.
[a] Additive and Ca(NTf2)2 were added to
(0.4 mmol) in CH3NO2 (2 mL) and stirred at 408C for 12 h; [b] yield of iso-
lated product.
1 (0.48 mmol) and 2a
high reactivity of the vinyl cation intermediate allowed for
smooth conversion of deactivated arenes bearing Br and even
F (Table 4, 3u and 3v). In addition, naphthyl and heteroaro-
matic groups gave excellent yields (Table 4, 3w and 3x).
Experimental Section
General procedure for the carboarylation: 1a (0.48 mmol) and 2a
(0.4 mmol) were dissolved in CH3NO2 (2 mL), then Bu4NPF6
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Acknowledgements
We are grateful for financial support by the China Scholarship
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Keywords: alkynes
methods · tetrasubstituted alkenes
· calcium · carboarylation · synthetic
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Received: December 16, 2014
Revised: January 28, 2015
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Published online on && &&, 0000
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Communication
COMMUNICATION
&
Carboarylation
L. Fu, M. Niggemann*
&& – &&
Calcium-Catalyzed Carboarylation of
Alkynes
Finally free: The first transition-metal-
free one-step synthesis of highly con-
gested, all-carbon tetrasubstituted ole-
fins has been realized by a calcium-cata-
lyzed carboarylation reaction. Internal
alkynes react with alcohols as alkylating
reagent under mild reaction conditions,
which provides access to a variety of
useful structural scaffolds via highly re-
active trisubstituted vinyl cations.
An environmentally benign
calcium catalyst…
…effects the first transition-metal-
free carboarylation of alkynes with
commercial and readily available
alcohols as alkylating agents. In
their Communication on page &&
ff., L. Fu and M. Niggemann report
a novel protocol for the one-step
synthesis of highly congested, all-
carbon tetrasubstituted alkenes,
with a wide substrate scope, good
functional-group tolerance and
simple experimental operation
under mild reaction conditions.
Chem. Eur. J. 2015, 21, 1 – 5
www.chemeurj.org
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ