Rearrangements of propargylic esters can be induced by some electrophiles

Article abstract of DOI:10.1021/ol5007778

An electrophile-induced rearrangement of propargylic esters without need of transition catalysis is possible. In particular, this observation provides a mild, economic, and effective method for the introduction of benzyl ether derivatives to access functionalized α,β-unsaturated ketones. Preliminary mechanistic studies suggest that this rearrangement undergoes an intramolecular 1,3-acyloxy shift.

Full text of DOI:10.1021/ol5007778

Letter
pubs.acs.org/OrgLett
Rearrangements of Propargylic Esters Can Be Induced by Some
Electrophiles
̌
Inga Cikotiene*
̇
Department of Organic Chemistry, Faculty of Chemistry Vilnius University Naugarduko 24, LT-03225 Vilnius, Lithuania
S
* Supporting Information
ABSTRACT: An electrophile-induced rearrangement of propargylic esters without
need of transition catalysis is possible. In particular, this observation provides a mild,
economic, and effective method for the introduction of benzyl ether derivatives to
access functionalized α,β-unsaturated ketones. Preliminary mechanistic studies
suggest that this rearrangement undergoes an intramolecular 1,3-acyloxy shift.
ropargylic esters are a specific class of alkynes with
interesting chemical behavior. It is known that these
substrates are able to undergo a transition-metal-catalyzed 1,2-
or 1,3-acyloxy shift leading to the formation of metal vinyl
carbenoid species or metal allenic intermediates, poised for
subsequent functionalization to give a huge variety of important
products (Scheme 1).1 Thus, 1,2-migration opens possibilities
should be noted that in all successful cases formation of 2-
substituted 1-(4-methoxyphenyl)prop-2-en-1-ones 2 was de-
tected (Scheme 2). The results obtained are summarized in
Table 1.
P
Scheme 2. Reaction between 3-(4-Methoxyphenyl)prop-2-
ynyl Acetate 1a and Electrophiles
Scheme 1. Metal-Mediated 1,2- and 1,3-Acyloxy Shifts of
Propargylic Esters
First, molecular iodine was chosen as an electrophilic reagent.
After stirring of the reaction mixture in DCM at room
temperature and full conversion of the starting material, two
products were isolated. The major one was the result of simple
electrophilic addition to the triple bond; however, some small
amount of 2-iodo-1-(4-methoxyphenyl)prop-2-en-1-one 2a was
also isolated (entry 1). While use of iodine monochloride gave a
slightly higher yield of desired product (entry 2), other sources of
electrophilic iodine, such as the Barluenga reagent or NIS, were
not successful. Phenylselenyl chloride underwent electrophilic
addition reaction to the triple bond of the starting material and
did not induce the desired rearrangement (entry 3).
After these not very exciting starting experiments, attention
was switched to ethers as potential sources of oxocarbenium ions.
Entry 4 represents the only one more or less successful example
of tetrahydrofuran modification. Although there are a number of
literature reports about tetrahydrofuran C−H modification via a
for “carbene-type” reactivity; for example, cyclopropanation
reactions or C−H insertions.2 On the other hand, 1,3-acyloxy
shift results in formation of nucleophilic allenes easily trapped by
electrophilic reagents by intra- or intermolecular processes.3
It was envisioned, that propargylic esters being representative
of nucleophilic alkynes could be able to react with electrophilic
reagents forming ionic intermediates. Then an ester carbonyl
group could participate in stabilization of vinylic carbocations by
forming 6- or 5-membered ionic intermediates. This reactivity
mode would give a precedent for electrophile initiated 1,3- or 1,2-
acyloxy shifts and therefore would considerably extend the
synthetic utility of propargylic esters.
This hypothesis was verified by choosing 3-(4-
methoxyphenyl)prop-2-ynyl acetate 1a as a model substrate
and investigation of its reactivity toward various electrophiles. It
Received: March 14, 2014
Published: April 2, 2014
© 2014 American Chemical Society
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Table 1. Data on the Reaction between 3-(4-Methoxyphenyl)prop-2-ynyl Acetate 1a and Electrophilic Reagents
a
b
c
An electrophilic addition reaction to the triple bond occurred concurrently. Only electrophilic addition reaction took place. Low conversion of the
starting material was reached.
single-electron-transfer process,4 in the present case most of
these methodologies (radical initiator together with transition-
metal salt as SET oxidant) did not give any satisfactory results. It
is also known that 2,3-dichloro-5,6-dicyanobenzoquinone
(DDQ) is able to promote a single-electron transfer followed
by H-abstraction from benzylic ethers, thus causing formation of
aryloxycations, stabilized by stereoelectronic effects.5 Indeed,
when a solution of the starting material with isochromane and an
equivalent of DDQ was stirred in dichloromethane at room
temperature, a trace formation of product was observed by TLC
after 24 h (entry 5).
Increasing the reaction temperature improved conversion and
led to 51% and 69% yields of 2c during reflux or irradiation of
dichloroethane solutions in a microwave oven (entries 6 and 7).
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Moreover, on one hand, it was found that catalytic amounts of
copper or silver triflates initiated reaction between starting alkyne
and isochromane effectively even at room temperatures (entries
8 and 9), and on the other hand silver nitrate, gold(III) chloride,
and copper iodide were proven to be totally ineffective (entries
10−12). Benzyl methyl ether was less reactive than isochromane
but also underwent DDQ- and triflate-promoted C(sp3)−C(sp2)
forming reaction (entries 13−15).
mechanism of the rearrangement, where 3-aryl moiety is crucial
for the stabilization of charge deficiency.
A plausible mechanism of an electrophile-induced trans-
formation of 3-arylprop-2-ynyl acetates is presented in Scheme 3.
Scheme 3. Proposed Mechanism for Electrophile-Induced
Rearrangement of 3-Arylprop-2-ynyl Acetates
The role of copper and silver triflate was checked by TLC and
13C NMR monitoring of starting 3-(4-methoxyphenyl)prop-2-
ynyl acetate 1a solution in dichloromethane-d2 during prolonged
(48−72 h) interaction with catalyst. Any changes of the starting
alkyne were not observed by TLC, and any sufficient
complexation between 3-(4-methoxyphenyl)prop-2-ynyl acetate
1a and silver triflate was not observed by 13C NMR spectroscopy.
Therefore, it was presumed that the crucial role of copper and
silver triflate for the promotion of the reaction is in formation of
the carboxonium triflate ion pair.6 This hypothesis was
undoubtedly supported by reaction between 3-(4-
methoxyphenyl)prop-2-ynyl acetate 1a and 1-methoxyisochro-
mane in the presence of 1 equiv of trimethylsilyl triflate.7 To our
pleasant surprise, the reaction was efficiently accomplished just in
5 min, resulting 90% yield of 2c (entry 16).
Optimized reaction conditions (entries 15 and 16) were
applied for the synthesis of 2-substituted 1-arylprop-2-en-1-ones
2. The results are summarized in Figure 1. It should be noted that
Oxocarbenium ions formed either from benzylic ethers during
2,3-dichloro-5,6-dicyanobenzoquinone-mediated single electron
transfer or trimethylsilyl triflate initiated cleavage of isochromane
acetal are easily trapped by the triple bond of the starting 3-
arylprop-2-ynyl acetates 1. After formation of ionic intermediates
I, a subsequent nucleophilic attack of the ester carbonyl occurs
leading to 6-membered carbocations II. Cleavage of the 6-
membered intermediates takes place together with loss of acetyl
group, promoted by a nucleophilic particle (i.e., water from the
atmosphere or methoxygroup from isochromane acetal).
Very recently, Hashmi et al. reported on a gold-initiated
intermolecular C(sp3)−C(sp2) bond-forming reaction involving
rearrangement of propargylic esters to nucleophilic allenes and a
subsequent reaction with electrophilic oxocarbenium ions
(Scheme 4).8 In contrast to the observation of Hashmi et al.,
Scheme 4. Gold-Catalyzed Protocol for the Preparation of
Isochromane Derivatives, Proposed Recently by Hashmi et al.
Figure 1. Compounds prepared via electrophile induced rearrangement
of 3-arylprop-2-ynyl acetates.
reaction rate is affected by the substituent next to the triple bond.
Thus, electron-donating groups on aromatic rings shortened
reaction times up to 3−5 min, while in the case of 3-phenylprop-
2-ynyl acetate 1b or 3-(4-chlorophenyl)prop-2-ynyl acetate 1c
1−1.5 h is required for full conversion of the starting materials. 4-
Arylbut-3-yn-2-yl acetates 1e,g and 1,3-diphenylprop-2-ynyl
acetate 1f after the trimethylsilyl triflate promoted treatment
with 1-methoxychroman formed mixtures of E- and Z-isomers
2j−l. However, aliphatic pent-2-ynyl acetate did not participate
in electrophilic rearrangements. This fact supports ionic
4-phenylbut-3-yn-2-yl acetate 1e under reaction conditions
formed major E-isomer 2j. However, other 1-substituted 3-
arylprop-2-ynyl acetates 1f,g underwent unselective rearrange-
ment to E- and Z-isomers. This fact supports that in the present
case 1,3-acyloxy shift occurs by different mechanism, excluding
formation of intermediate allenes. Although the electrophilic
rearrangement of 1-substituted 3-arylprop-2-ynyl acetates is not
a diastereoselective process, for the linear substrates this
methodology represents a very mild, economic, and efficient
process for preparation of ethers of Morita−Baylis−Hillman
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adducts (compounds 2c−i) since it does not require use of
expensive gold and silver complexes.
̌
002). Mrs. Ieva Karpaviciene (Vilnius University) is kindly
̇
acknowledged for the synthesis of O-labeled 3-(4-methoxyphen-
yl)prop-2-ynyl acetate 1a-18O.
For the confirmation of the proposed mechanistic scenario, an
isotopic labeling experiment was designed and conducted.
Labeled 3-(4-methoxyphenyl)prop-2-ynyl acetate 1a-18O was
synthesized by the Steglich esterification9 between the
corresponding 3-(4-methoxyphenyl)prop-2-ynyl alcohol and
18O-labeled acetic acid. With substrate 1a-18O in hand, the
trimethylsilyl triflate catalyzed reaction with isochromane acetal
was conducted and the product 2c-18O was obtained in 89% yield
without any loss of 18O, as it was determined by the HRMS
spectrum. Moreover, an observed δ = 0.05 ppm (5 Hz) upfield
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Figure 2. Isotopic labeling experiment and fragment of 13C NMR
spectra of 2c-18O.
In summary, it was shown that 1,3-acyloxy shift in propargylic
esters can be induced by some electrophiles. It is the first example
of electrophilic isomerization of propargylic esters without need
of gold catalysis,11 and this reactivity mode points toward a broad
and divergent applicability of the propargylic substrates for the
synthesis of synthetically and biologically useful α,β-unsaturated
ketones. Further experimental and theoretical investigations of
these methodologies are underway in our laboratory and will be
published in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, product characterization and copies of
1H and 13C NMR spectra of all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: inga.cikotiene@chf.vu.lt.
Notes
(11) During preparation of this manuscript, an indium chloride
catalyzed alkylative rearrangement of propargylic acetates was
published: Onishi, Y.; Nishimoto, Y.; Yasuda, M.; Baba, A. Org. Lett.
2014, 16, 1176.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The project was supported by the European Social Fund under
the Global Grant measure (Grant No. VP1-3.1-SMM-07-K-01-
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