Tandem Transformations via Friedel-Crafts Acylation Followed by a Ring-Expansion, Ring-Opening, and Cycloisomerization Sequence

Article abstract of DOI:10.1021/acs.orglett.8b03881

A tandem synthetic route to a diverse array of cyclic compounds has been developed from Friedel-Crafts acylation of alkynes followed by the microwave irradiation of β-chlorovinyl ketone intermediates. The stereoisomeric β-chlorovinyl ketone intermediates smoothly underwent a thermal α-vinyl enolization and ring expansion to vinyl and carbocyclic furans as well as cyclopetene derivatives in good to excellent yields without the need for any catalysts.

Full text of DOI:10.1021/acs.orglett.8b03881

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Tandem Transformations via Friedel−Crafts Acylation Followed by a
Ring-Expansion, Ring-Opening, and Cycloisomerization Sequence
Hun Young Kim and Kyungsoo Oh*
Center for Metareceptome Research, College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak, Seoul 06974, Republic
of Korea
S
* Supporting Information
ABSTRACT: A tandem synthetic route to a diverse array of
cyclic compounds has been developed from Friedel−Crafts
acylation of alkynes followed by the microwave irradiation of
β-chlorovinyl ketone intermediates. The stereoisomeric β-
chlorovinyl ketone intermediates smoothly underwent a
thermal α-vinyl enolization and ring expansion to vinyl and
carbocyclic furans as well as cyclopetene derivatives in good to
excellent yields without the need for any catalysts.
β-Chlorovinyl ketones, readily accessible from the Friedel−
Crafts acylation of alkynes, represent a special domain of
functional molecules with a unique reaction profile and
versatile synthetic utility.1 In contrast to other α,β-unsaturated
carbonyl systems, the (E)-β-chlorovinyl ketones readily
undergo a facile α-vinyl enolization in the presence of a mild
base, Et3N, at ambient temperature (Scheme 1).2 This reaction
synthetic utility of (Z)-β-chlorovinyl ketones via the α-vinyl
enolization strategy remains largely unexplored.
Motivated by the α-vinyl enolization pathway of β-
chlorovinyl ketones, we aimed to discover new synthetic
methods that showcase the α-vinyl enolization-driven skeletal
rearrangements of β-chlorovinyl ketones. As the conformations
of stereoisomeric β-chlorovinyl ketones were projected to
influence the initial α-vinyl enolization pathway, the thermal
conditions could, in principle, increase access to high-energy
conformations/stereoisomers of β-chlorovinyl ketones.
Although no previous attempt had been made for such α-
vinyl enolization of α,β-unsaturated carbonyl systems,4 the fact
that the alkene isomerization could be performed via
conformational and stereochemical changes under thermal
conditions strengthened our hypothesis on the thermal α-vinyl
enolization of β-chlorovinyl ketones. To capitalize on micro-
wave-assisted superheating methods, β-chlorovinyl ketones
were heated under microwave irradiation by varying reaction
solvent, temperature, and time (see the Supporting Informa-
tion for the detailed optimization methods and reaction
mechanism studies). The final optimization condition of the
thermal α-vinyl enolization of β-chlorovinyl ketones included
the irradiation of β-chlorovinyl ketones for 30 min at 250 °C
(Scheme 2).
Scheme 1. α-Vinyl Enolization of β-Chlorovinyl Ketones
and Their Synthetic Utility
The tandem transformation of acid chlorides 1 and alkyne 2
to furans 3 via the intermediacy of β-chlorovinyl ketones under
microwave irradiation was found to be general (Scheme 3).
The electronic feature of the acid chloride R1 did not influence
the reaction outcome, providing good to excellent isolated
yields of furans 3a−3g over two steps. The structural variation
of the alkyne R2 group was also tolerated where furans with a
variety of functional groups such as alkyl chloride 3i−j, ester
moiety 3k, and phthalimide 3l were smoothly formed. In
pathway has paved a way to generate versatile synthetic
intermediate species with on demand reactivity, nucleophilic or
electrophilic, where the characteristics of reacting partners
could be modulated.3 The planar conformation of (Z)-β-
chlorovinyl ketones displays an α-vinyl enolization significantly
slower than that of (E)-β-chlorovinyl ketones, and the reaction
under increased temperature competitively produces the
quaternary salts through the Michael addition of Et3N to
(Z)-β-chlorovinyl ketones.2 Thus, at the present time, the
Received: December 5, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03881
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Scheme 2. Thermal α-Vinyl Enolization of β-Chlorovinyl
Ketones
Scheme 4. Ring Expansion and Ring Opening to Furan
Derivatives
Scheme 3. Enolization and Cycloisomerization Sequence to
Furan Derivatives
chlorovinyl ketones in 48−73% yields. Mechanistically, we
propose a reaction sequence of the microwave-assisted
cyclopropyl opening followed by dehydrochlorination to
cyclobutyl-fused furan 4-C. A subsequent isomerization
followed by cyclobutenyl opening under microwave heating
conditions leads to 4-vinylfuran product.5 Previously, the α-
substituted 3-cyclopropylideneprop-2-en-1-ones were trans-
formed to furan-fused cyclobutenes under the PdCl2-catalyzed
cycloisomerization conditions.6 Whereas furan-fused cyclo-
butenes readily opened up the furan moiety under the
oxidative conditions (i.e., chemical-driven transformation),
the current synthetic access to 4-vinylfurans from (E)-β-
chlorovinyl ketones maintained the furan moiety, illustrating
the unique microwave-assisted heating method.
The introduction of a cyclobutyl group to β-chlorovinyl
ketones was next considered because the ring strain of
cyclobutanes is comparable to that of cyclopropanes.7 Starting
from the Friedel−Crafts acylation of ethynylcyclobutane 2j,
the subjection of a mixture of β-chlorovinyl ketone
intermediates under the microwave irradiation provided a 4:1
mixture of cyclopent-en-1-ylidenes 6 in a synthetically useful
level of 48−72% yields (Scheme 5). The ratio of stereoisomers
6 was consistent regardless of the substitution pattern, thus it is
conceivable that the equilibrium between (E)-6 and (Z)-6 has
been established. One possible driving force to such
equilibrium might lie in the isomerization-driven process via
6-D and 6-E to the stereoisomeric 6. Mechanistically, as the
possible formation of cyclopentyl-fused furan has been
postulated from the corresponding alleneyl ketone upon flash
vacuum thermolysis at 800 °C,8 it is reasonable to speculate
the cyclobutane expansion to cyclopentyl-fused furan 6-C
thermally isomerizes to the more stable forms of compounds,
cyclopent-en-1-ylidenes 6. It should be noted that the current
addition, the introduction of an alkyl group R1 was also
possible, providing a 2,5-dialkyl-substituted furan 3m in a 71%
yield. It should be noted that the current furan synthesis from a
mixture of β-chlorovinyl ketones represents a nonmetal,
reagentless, and rapid cycloisomerization method develop-
ment.
Given that the β-chlorovinyl ketones were smoothly
transformed to the allenyl ketones under microwave-assisted
heating conditions, the β-chlorovinyl ketones with a cyclo-
propyl group were subjected to the microwave irradiation
(Scheme 4). After some experimentation, it was found that
(E)-β-chlorovinyl ketones 4 with a cyclopropyl group
proceeded in the desired tandem reaction sequence to give
the corresponding 4-vinylfuran derivatives 5, whereas the (Z)-
4b only reluctantly underwent water addition reaction to give
4ba (recovered unreacted (Z)-4b in 70%). Thus, the
cyclopropyl-substituted (E)-β-chlorovinyl ketones were iso-
lated and then subjected to microwave irradiation conditions.
In this way, a general synthetic route to 4-vinylfuran was
established from a tandem reaction sequence from (E)-β-
B
DOI: 10.1021/acs.orglett.8b03881
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Scheme 5. Ring Expansion to Cyclopent-2-en-1-ylidene
Derivatives
Scheme 6. Ring Expansion/Cycloisomerization to
Cyclohexyl-Fused Furans
Scheme 7. Isomerization to Dienyl Ketones
synthetic approach represents a step-economical synthetic
method to cyclopent-2-en-1-ylidene derivatives.
The ring-expansion/isomerization strategy has been ex-
tended to β-chlorovinyl ketones with a cyclopentyl group
(Scheme 6). Thus, starting from the Friedel−Crafts acylation
of ethynylcyclopentane 2k, the substrate scope of the reaction
sequence was broad enough to include a thiophenyl-containing
furan 7i and an alkyl-substituted furan 7j. The exclusive
formation of cyclohexyl-fused furans suggests the involvement
of cyclopentyl expansion to 7-B followed by dehydrochlorina-
tion. Also, as our control experiment using cyclopentyl-
substituted allenyl ketone 7-C confirmed the facile cyclo-
isomerization pathway to cyclohexyl fused furan 7a under the
microwave heating conditions at 180 °C, the vinyl enolization
of β-chlorovinyl ketones followed by cycloisomerization
pathway is equally possible. In contrast to the gold-catalyzed
cycloisomerization of allenyl ketones to cyclohexyl-fused
furans,9 the microwave-assisted heating conditions smoothly
cycloisomerize cyclopentyl-substituted allenyl ketones to
cyclohexyl-fused furans 7 via a thermal ring-expansion
strategy.10
The use of cyclohexyl-substituted β-chlorovinyl ketones did
not provide the ring-expansion/cycloisomerization products.
Instead, the formation of dienyl ketones (E,E)-8 was
accomplished in 65−81% yields (Scheme 7).11 As our control
experiment confirmed a facile isomerization of cyclohexyl-
substituted allenyl ketone to dienyl ketone (E,E)-8a under
microwave-assisted heating conditions in 3 min, a plausible
reaction pathway to dienyl ketones from β-chlorovinyl ketones
is presented. Thus, after the Friedel−Crafts acylation of
ethynylcyclohexane 2l, the dehydrochlorination of β-chlor-
ovinyl ketones provides the cyclohexyl-substituted allenyl
ketones, undergoing either the thermal isomerization to dienyl
ketones 8 or the cycloisomerization-driven isomerization via 8-
A to dienyl ketone 8. Whereas the indium-catalyzed cyclo-
isomerization of cyclohexyl-substituted allenyl ketone to
cycloheptyl-fused furan has been reported to be 18% by
C
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NMR,12 our control experiment using an authentic sample of
cyclohexyl-substituted allenyl ketone (R1 = Ph) did not
provide cycloheptyl-fused furan under microwave conditions.
Exclusive formation of stereodefined dienyl ketones (E,E)-8
from the cyclohexyl-substituted allenyl ketones illustrates the
thermodynamic control under microwave-assisted heating
conditions.
Y. Stereoselective One-Pot Sequential Dehydrochlorination/trans-
Hydrofluorination Reaction of β-Chloro-α,β-unsaturated Aldehydes
or Ketones: Facile Access to (Z)-β-Fluoro-β-arylenals/β-Fluoro-β-
arylenones. Adv. Synth. Catal. 2017, 359, 4348−4358.
(2) Kim, H. Y.; Li, J.-Y.; Oh, K. Studies on Elimination Pathways of
β-Halovinyl Ketones Leading to Allenyl and Propargyl Ketones and
Furans under the Action of Mild Bases. J. Org. Chem. 2012, 77,
11132−11145.
In summary, we developed tandem synthetic transforma-
tions to a diverse array of building blocks from readily available
starting materials, alkynes and acid chlorides. With the
discovery of a microwave-assisted thermal α-vinyl enolization
of β-chlorovinyl ketones, the developed synthetic protocol
enables a rapid synthetic transformation of stereoisomeric β-
chlorovinyl ketones using ring-expansion, ring-opening, and
cycloisomerization strategies. The use of β-chlorovinyl ketones
under microwave-assisted heating conditions opens a new
venue for rapid and reagentless synthetic transformations with
short reaction times and clean reaction profiles.
(3) For the nucleophilic [3]cumulenols, see: (a) Kim, H. Y.; Li, J.-Y.;
Oh, K. A Soft Vinyl Enolization Approach to α-Acylvinyl Anions:
Direct Aldol/Aldol Condensation Reactions of (E)-β-Chlorovinyl
Ketones. Angew. Chem., Int. Ed. 2013, 52, 3736−3740. (b) Kim, H. Y.;
Lee, S.; Kim, S.; Oh, K. Regiodivergent Halogenation of (E)-β-
Chlorovinyl Ketones via Soft α-Vinyl Enolization Strategy. Org. Lett.
2015, 17, 450−453. (c) Song, E.; Kim, H. Y.; Oh, K. A Facile
Synthesis of 3,4-Dimercaptofurans via Sulfenylation of (E)-β-
Chlorovinyl Ketones and 1,2-Sulfur Migration. Org. Biomol. Chem.
2017, 15, 1776−1779. For the electrophilic [3]cumulenols, see:
(d) Kim, H. Y.; Rooney, E. O.; Meury, R. P.; Oh, K. Ambivalent
Reactivity Modes of β-Chlorovinyl Ketones: Electrophilic Lithium
[3]Cumulenolates from Soft Vinyl Enolization Strategy. Angew.
Chem., Int. Ed. 2013, 52, 8026−8030. (e) Kim, H. Y.; Oh, K. 1,3-
Dienones and 2H-Pyran-2-ones from Soft α-Vinyl Enolization of β-
ASSOCIATED CONTENT
* Supporting Information
■
S
̈
Chlorovinyl Ketones: Defined Roles of Bronsted and Lewis Base. Org.
Lett. 2015, 17, 6254−6257.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03881.
(4) For a base-promoted dehydrobromination under microwave
conditions, see Kuang, C.; Yang, Q.; Senboku, H.; Tokuda, M.
Synthesis of (Z)-1-Bromo-1-allenes and Terminal Alkynes from anti-
2,3-Dibromoalkanic Acids by Microwave-Induced Reaction. Tetrahe-
dron 2005, 61, 4043−4052.
Experimental procedures and characterization data for
all new compounds (PDF)
(5) We thank the reviewer for suggesting the reaction mechanisms
via the direct cycloalkyl ring expansion pathways of β-chlorovinyl
ketones.
(6) Miao, M.; Cao, J.; Zhang, J.; Huang, X.; Wu, L. PdCl2-Catalyzed
Oxidative Cycloisomerization of 3-Cyclopropylidenepro-2-en-1-ones.
Org. Lett. 2012, 14, 2718−2721.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kyungsoooh@cau.ac.kr.
ORCID
(7) The ring strain of cyclopropane is estimated to be 27.5 kcal/mol,
whereas that of cyclobutane is about 26.3 kcal/mol. See: Wiberg, K. B.
The Concept of Strain in Organic Chemistry. Angew. Chem., Int. Ed.
Engl. 1986, 25, 312−322.
Hun Young Kim: 0000-0002-8461-8910
Kyungsoo Oh: 0000-0002-4566-6573
Notes
(8) Jullien, J.; Pechine, J. M.; Perez, F.; Piade, J. J. Flash Vacuum
Thermolysis of β-Keto-trimethylsily-enol-ethers: Synthesis of Allenic
and Furanic Derivatives. Tetrahedron 1982, 38, 1413−1416.
(9) (a) Dudnik, A. S.; Gevorgyan, V. Metal-Catalyzed [1,2]-Alkyl
Shift in Allenyl Ketones: Synthesis of Multisubstituted Furans. Angew.
Chem., Int. Ed. 2007, 46, 5195−5197. (b) Miao, M.; Xu, H.; Jin, M.;
Chen, Z.; Xu, J.; Ren, H. 1,2-Gold Carbene Transfer Empowers
Regioselective Synthesis of Polysubstituted Furans. Org. Lett. 2018,
20, 3096−3100.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the National Research
Foundation of Korea (NRF) grants funded by the Korean
government (MSIP) (NRF-2015R1A5A1008958 and NRF-
2018R1D1A1B07049189).
(10) Chen, H.; Zhang, L. A Desulfurative Approach in Oxidative
Gold Catalysis: Regiospecific Access to Donor-Substituted Acyl Gold
Carbenes. Angew. Chem., Int. Ed. 2015, 54, 11775−11779.
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DOI: 10.1021/acs.orglett.8b03881
Org. Lett. XXXX, XXX, XXX−XXX