Cyclopentanone as a cation-stabilizing electron-pair donor in the calcium-catalyzed intermolecular carbohydroxylation of alkynes

Article abstract of DOI:10.1021/acs.orglett.5b00312

Although they have been used as reactivity-controlling additives in cationic polymerizations for decades, Lewis basic electron pair donor (ED) compounds were never used for the stabilization of cationic intermediates in transformations of small molecules. As such an ED, cyclopentanone proved highly efficient for the stabilization of allyl and vinyl cations in combination with our calcium-based catalyst system. Therefore, the first general transition-metal-free intermolecular carbohydroxylation of alkynes with allyl and propargyl alcohols was realized.

Full text of DOI:10.1021/acs.orglett.5b00312

Letter
pubs.acs.org/OrgLett
Cyclopentanone as a Cation-Stabilizing Electron-Pair Donor in the
Calcium-Catalyzed Intermolecular Carbohydroxylation of Alkynes
Tobias Stopka and Meike Niggemann*
Institute of Organic Chemistry, RWTH Aachen University, 52074 Aachen, Germany
S
* Supporting Information
ABSTRACT: Although they have been used as reactivity-
controlling additives in cationic polymerizations for decades,
Lewis basic “electron pair donor” (ED) compounds were never
used for the stabilization of cationic intermediates in trans-
formations of small molecules. As such an ED, cyclopentanone
proved highly efficient for the stabilization of allyl and vinyl
cations in combination with our calcium-based catalyst system.
Therefore, the first general transition-metal-free intermolecular
carbohydroxylation of alkynes with allyl and propargyl alcohols was realized.
Scheme 2. Ether Cation Equilibrium
he direct functionalization of alkynes with carbon-
centered electrophiles represents a highly desirable yet
T
scarcely explored C−C bond-formation reaction.1 A challeng-
ing model transformation for this type of chemistry is the
carbohydroxylation with inexpensive and readily available
alcohols resulting in the formation of ketones.1d,2 As outlined
in Scheme 1, this process consists of four elementary steps: (1)
ionization of the alcohol; (2) nucleophilic attack of the alkyne
and formation of a vinyl cation intermediate; (3) interception
of the vinyl cation with a water molecule; (4) keto enol
tautomerization.
Even though fundamentally simple and benefiting from full
atom economy, the process suffers from major limitations
related to the first two of these elementary steps. First, only
very few catalysts have been found competent for the direct
ionization of alcohols 1 other than benzylic alcohols; the scope
of the process with regard to the carbon electrophile A remains
therefore severely limited,1d,2f−l and stoichiometric use of
“catalyst” is often necessary. Even more difficulties are
associated with the low nucleophilicity of the alkyne moiety
in 2.3 Due to this low nucleophilicity, the addition of the alkyne
2 to the previously generated carbocation A tends to be
relatively slow, particularly in intermolecular transformations,
so that the cation A is very likely to be entangled in
unproductive side reactions especially when highly reactive
due to the absence of stabilizing substituents. Furthermore, the
reactive intermediate that is formed upon the successful
addition, the vinyl cation B, is in any case even more reactive
than A and its fate, hence, even more difficult to control.
In recent years, our group has focused on the development of
a simple calcium catalyst as a more sustainable alternative to
expensive and highly toxic noble metal catalysts in synthetic
chemistry.4 Decorated with a carefully balanced combination of
noncoordinating anions, the Ca2+ ion was found to be a highly
efficient Lewis acid catalyst for the direct ionization of readily
available and also nonbenzylic alcohols. In addition, cation
formation was found to be generally accompanied by a
reversible background reaction in which the cation was found
to form ethers 4 (see Scheme 2),5 thereby maintaining the
effective cation concentration at a low level that might be highly
beneficial to avoid unproductive side reactions of cation A.
Thus, having in hand a competent catalyst for the formation
of an unprecedented scope of carbocations from alcohols and
to maintain an equilibrium between these and a stable resting
state, we set out to identify further reaction parameters that also
allow for a reversible stabilization of the vinyl cation B. An
extensive survey of the literature pointed us toward a series of
papers that discusses the beneficial influence of electron-pair
donors (EDs) for the control of reactivity in cationic
polymerizations reactions.6 Although the exact mechanistic
role of these EDs is still a subject of debate, it was uniformly
found that the rate of polymerization was slowed in the
presence of EDs and at the same time products of a more
controlled process with fewer unwanted intramolecular self-
alkylation and smaller molecular weight distributions were
Scheme 1. Carbohydroxylation of Alkynes
Received: January 30, 2015
Published: March 5, 2015
© 2015 American Chemical Society
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Table 1. Optimization of the Reaction Conditions
Table 2. Addition of Alcohols to Phenylacetylene
a
Catalyst (5 mol %) and additive (15 mol %) were added to alcohol
1a (0.25 mmol) and alkyne 2a (0.75 mmol) in DCE (2.5 mL) and
b
stirred for 16 h. Isolated yield.
provided. This clearly points toward a reduction of reactivity of
the cationic propagating species by the formation of Lewis
acid/base pairs between the cation center and the lewis basic
ED with more or less covalent character.7
Inspired by these findings from polymer chemistry, we chose
the addition of phenylethanol (1a), yielding a still relatively
stable benzylic cation, to phenylacetylene (2a) as a starting
point to test the influence of EDs on the title transformation. In
an initial set of screening reactions, 5 mol % of Ca(NTf2)2 in
the presence of 15 mol % of NH4PF6 proved to be the most
effective catalyst system in the absence of EDs, yielding the
desired product in 25% yield (Table 1, entry 1).
Even though they are generally competent for the first
ionization step in this particular case, as it is a benzylic alcohol,
commonly employed Lewis acids (Table 1, entries 2 and 3) as
well as Brønsted acids (Table 1, entries 4 and 5) were less
efficient than the calcium-based system and led to complex
reaction mixtures. The addition and variation of additives such
as NH4PF6 had no significant impact in combination with these
catalysts. Further optimization confirmed that the presence of
cyclopentanone significantly improved the results, and the
desired product was isolated in a much better yield (Table 1,
entry 8). Notably, if the reaction was carried out in other
solvents or with an additive different from NH4PF6 (Table 1,
entries 9 and 10) the reaction became sluggish again. Finally,
slightly higher reaction temperatures (40 °C) afforded the
product with excellent yield (Table 1, entry 11).
a
Ca(NTf2)2 (5 mol %) and NH4PF6 (15 mol %) were added to
alcohols 1b−l (0.25 mmol), alkyne 2a (0.75 mmol), and cyclo-
pentanone (1.25 mmol) in DCE (2.5 mL) and stirred for the indicated
b
c
time at room temperature. Isolated yield. Reaction at 40 °C.
d
e
Mixture of regioisomers (see the Supporting Information). 10 equiv
of alkyne was used.
Although other carbonyl compounds had the ability to
stabilize intermediates as well, inferior results were obtained in
comparison with cyclopentanone (Table 1, entries 12 and 13).
As these results reflect the carbonyl oxygens’ binding affinity to
Lewis acids, PhCHO ≈ PhCOMe < cyclopentanone, the
influence of dimethylformamide and tetramethylurea was
analyzed.7,8 The presence of these two compounds with an
even higher Lewis acid binding affinity resulted in the
suppression of the formation of ether 4 (cf. Scheme 2),
therefore leading to oligomerization of the initially formed
cation A. This finding indicates once more the importance of a
meticulous balancing of all stabilizing effects. Interestingly, the
addition of carbonyl compounds had little influence in reactions
catalyzed by the common Lewis/Brønsted acids in entries 2−5.
Having in hand the optimized reaction conditions, the
generality and scope of the reaction were explored. Therefore, a
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be used without a drop in yield or expanded reaction times
(entry 3). In addition, electron-deficient alkynes reacted
smoothly, albeit with a slightly diminished yield.
Table 3. Reaction of 2-Cyclohexenol with Phenylacetylenes
In summary, we demonstrate that cyclopentanone, as a
weakly Lewis basic electron-pair donor, proves to be highly
efficient for the stabilization of allyl and vinyl cation
intermediates in combination with our calcium-based catalyst
system. Therefore, a transformation that is typically plagued by
side reactions originating in the fleeting nature of poorly
stabilized cationic intermediates, the intermolecular carbohy-
droxylation of alkynes, was realized with allyl and propargyl
alcohols as alkylation agents for the first time. Further
investigations in our laboratories of the stabilizing influence
of electron-pair donors in other transformations of small
molecules with cation participation will be reported due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, full characterization of products,
NMR spectra, and additional information. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: niggemann@oc.rwth-aachen.de.
Notes
a
The authors declare no competing financial interest.
Ca(NTf2)2 (5 mol %) and NH4PF6 (15 mol %) were added to 2-
cyclohexenol 1m (0.25 mmol), phenylacetylene 2a−f (0.75 mmol),
and cyclopentanone (1.25 mmol) in DCE (2.5 mL) and stirred for the
time indicated at room temperature.
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