Base-catalyzed domino cyclization of acetylenes with ketones to functionalized cyclopentenes

Article abstract of DOI:10.1021/ol501881e

Acetylene reacts with methylaryl(hetaryl)ketones in the presence of 6.5 mol % KOH in DMSO to give diastereoselectively in single operationally functionalized cyclopentenes. This domino cyclization involving two molecules of acetylene and two molecules of

Full text of DOI:10.1021/ol501881e

Letter
pubs.acs.org/OrgLett
Base-Catalyzed Domino Cyclization of Acetylenes with Ketones to
Functionalized Cyclopentenes
Elena Yu. Schmidt,† Boris A. Trofimov,*,† Ivan A. Bidusenko,† Natalia A. Cherimichkina,†
Igor’ A. Ushakov,† Nadezhda I. Protzuk,† and Yurii V. Gatilov‡,§
†A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky Str., 664033 Irkutsk, Russia
‡N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, 9 Lavrentiev Str.,
630090 Novosibirsk, Russia
§Novosibirsk State University, 2 Pirogov Str., 630090 Novosibirsk, Russia
S
* Supporting Information
ABSTRACT: Acetylene reacts with methylaryl(hetaryl)ketones in the
presence of 6.5 mol % KOH in DMSO to give diastereoselectively in
single operationally functionalized cyclopentenes. This domino cycliza-
tion involving two molecules of acetylene and two molecules of ketone
proceeds with the formation of four C−C bonds. The complementary
assembly of the cyclopentenes with similar functionalities from acetylenes
and 1,5-diketones has been developed.
he discovery of new reactions which led to the formation of
the C−C bonds, particularly several ones constituting
T
pharmaceutically and synthetically important structures via a
single-pot methodology, is a well-recognized challenge of organic
chemistry.1 Alkynes due to their exceptionally high and
multifaceted reactivity are especially rewarding materials2 for
such reactions as cyclotrimerization,2a,3 cyclotetramerization,2a
pyridine,2a,3c,4 and pyrrole5 synthesis. Currently, this goal is
successfully achieved with the help of transition-metal-based
catalysts.2−5 Along this avenue, less common are cascade
assemblies of cyclic structures with participation of alkynes and
appropriate nucleophile in the presence of bases (most often
such as alkaline metal hydroxide or alkoxide/DMSO systems).6
Among such domino type reactions are one-pot syntheses of
pyrroles,6,7 7-methylene-6,8-dioxabicyclo[3.2.1]octanes (A),8
Δ2-isoxazolines (B),9 δ-carboline,10 4-methylene-3-oxa-1-azabi-
cyclo[3.1.0]hexanes (C),11 azulenones (D),12 and functionalized
thiophenes E13 (representative examples are given in Figure 1).
Here we report on a serendipitous finding that, in the presence
of minor amounts of KOH in DMSO, two molecules of acetylene
1a and two molecules of ketones 2 upon moderate heating are
diastereoselectively assembled to functionalized cyclopentenes 3
in a yield of up to 63% (Table 1). After careful investigation of the
reaction features, we have selected 6.5 mol % KOH (relative to
ketone 2), 70 °C, and 8 h to be near to optimal conditions for the
synthesis of cyclopentenes 3.
Figure 1. Representative products of the base-promoted domino
reactions of acetylenes with ketones and other reactants.
The structure of cyclopentenes unambiguously follows from
single-crystal X-ray analysis of one of their representatives, 3a
(Figure 2).
A five-membered cycle of molecule 3a is in envelope
conformation and the C(4) atom is deviated by 0.320(2) Å
from the plane of other atoms. The benzoyl fragment is
nonplanar, the torsion angle O(1)C(6)C(7)C(12) being
30.5(2)°. The carbonyl moiety is out of plane of the double
bond [the torsion angle C(2)C(1)C(6)O(1) equals 52.6(2)°].
In the crystal, the molecules are bonded in chains by H-bonding
O(2)−H···O(1) [the distance H···O is 1.96(2) Å; the angle O−
H···O is 173(2)°].
The reaction is commonly carried out with excess acetylene
under pressure in a closed reactor. The initial acetylene pressure
at ambient temperature is 12−14 atm, reaching its maximum
(∼16−18 atm) at the reaction temperature and then dropping as
the reaction progresses.
It is important that cyclopentenes 3 are formed exclusively as
single diastereomers; i.e., the reaction is strictly stereoselective.
Received: June 29, 2014
Published: July 23, 2014
© 2014 American Chemical Society
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yields of 3 range from 51% to 63%. Under these conditions, the
conversion of the starting ketones 2 is close to 100%. In the
reaction mixtures, there are always some amounts of 7-
methylene-6,8-dioxabicyclo[3.2.1]octanes A (Figure 1), easily
separated from the major products by column chromatography.
In the case of 4-acetylpyridine 2d, the reaction proceeds with
the complete loss of the pyridyl carbonyl function to deliver
cyclopentene 4d.
Table 1. Substrate Scope and the Products Yield for the
Reaction of Acetylene 1a with Ketones 2a−e in the Presence
a
of the KOH/DMSO System
The key intermediate of the cascade formation of cyclo-
pentenes 3 is believed to be 1,5-diketone 5,8b which further
undergoes the Favorsky ethynylation and subsequent ring
closure of the acetylenic ketoalcoholate 6 (Scheme 1). The
Scheme 1. A Plausible Pathway for the Cascade Formation of
Cylcyclopentenes 3
a
Reaction conditions: initial pressure of acetylene 1a at ambient
temperature was 12−14 atm (stirred reactor), ketone 2 (17.0 mmol),
b
KOH·0.5H2O (0.07 g, 1.1 mmol), DMSO (50 mL). Isolated yield
after column chromatography (basic Al2O3, hexane−CHCl3). The
reaction was carried out using 50 mol % of KOH at 80 °C.
intermediate 5 may result from the nucleophilic addition of two
molecules of a ketone to acetylene (first, C-vinylation of the
ketone, then prototropic rearrangement of the adduct, and the
Michael addition of the second molecule of deprotonated ketone
to α,β-unsaturated ketone). The cyclization of intermediate 6 to
cyclopentane 8 likely occurs via the nucleophilic addition of
carbon-centered anion 7 to the triple bond (Scheme 1). A likely
model of the diastereoselectivity of the reaction is the template
effect of the potassium cation which retains enolizable carbonyl
function and a hydroxyl group on one side of the closing ring,
though this will be a subject of our special investigation.
Thus, this assembling involves the formation of four C−C
bonds in one synthetic operation.
c
According to Scheme 1, cyclopentenes 3 might also be
assembled from acetylenes and 1,5-diketones 5 are readily
available via the condensation of aldehydes with two molecules of
ketones.14 Indeed, it came true. The reaction of acetylenes 1a,b
with 1,5-diketones 5a−c has been conducted under the best
conditions selected from numerous experiments, in which the
major reaction parameters (the catalyst and reactant concen-
tration, reaction temperature, and time) are varied (Table 2).
These conditions allow the complete conversion of 1,5-diketones
5.
Figure 2. X-ray structure of cyclopentene 3a (crystal grown from Et2O;
CCDC 986429).
The 1H and 13C NMR spectra and 2D NOESY spectra are in
agreement with the structure of 3a (Figure 3).
Table 1 shows that the assembly of cyclopentenes 3 from
acetylene and ketones tolerates both acetylarenes 2a−c and
acetylhetarenes 2d,e. For all the ketones studied, the isolated
From Table 2, it follows that the reaction is suitable for both
substituted acetylenes (such as phenylacetylene 1b) and diverse
1,5-diketones 5. Expectedly, yields of the products as well as
sometimes their structure depend remarkably on the substituents
in 1,5-diketone molecules.
As in the straightforward reaction of acetylene 1a with ketones
2 (Table 1), in certain cases, deacylation of cyclopentenes 3 takes
place (formation of cyclopentenes 4). The deacylation can be
Figure 3. Characteristic NOESY correlations for cyclopentene 3a.
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Table 2. Product Yields for the Reaction of Acetylenes 1a,b
with 1,5-Diketones 5a−c in the Presence of the KOH/DMSO
System
Scheme 2. Deacylation of Cyclopentenes 3 under the Action
of Hydroxide Anion
Scheme 3. Dehydration of Cyclopentene 4h to the
Cyclopentadiene 9h
acylpentenols but also to acyl-free cyclopentenes and -penta-
dienes.
The functionalized cyclopentenes are widely used pharma-
ceutical building blocks, e.g. to synthesize englerin A (a potent
inhibitor of renal cancer),15 neomangicol (cytotoxic agent
against human colon carcinoma),16 and trichodermone A
(antibacterial medicine).17 Cyclopentenes are common pre-
cursors of antiviral nucleosides,18 iridoids (natural sedative,
antimalarial, analgesic, and cytotoxic agents),19 and carbocyclic
nucleosides (active against cowpox and severe acute respiratory
syndrome virus).20 The molecules of carbovir, a potent inhibitor
of HIV-1 replication, and abacavir, a drug to combat AIDS,
contain a functionalized hydroxycyclopentene structural unit.21
The cyclopentenol moiety is a part of the nucleoside antibiotic
aristeromycin.22
The introduction of substituents, particularly functional ones,
into the cyclopentene ring remains a synthetic challenge. An
approach to 2,3-disubstituted hydroxycyclopentenes through
two consecutive additions of electrophiles to a cyclopentene
bisanionic synthon is recently reported.23 Aroylcyclopentenes
are formed via cyclizations of silyloxyenynes in the presence of
AuCl3 with phosphine ligands.24 Substituted cyclopentenols are
also synthesized by the enal−alkyne reductive cycloaddition in
the presence of a Ni complex.25 Nine steps are required to
synthesize benzyloxycyclopentenol starting from 2,3-O-isopro-
pylideneglyceraldehyde.26 Functionalized hydroxycyclopentenes
are prepared from unsaturated 1,6-dicarbonyl compounds in the
presence of secondary amines.27 Likewise, base-catalyzed
cyclization of unsaturated thiol esters containing an aldehyde
function furnishes functionalized cyclopentenols.28 In an earlier
work, it has been shown that the reduction of epoxide prepared
by the oxidation of cyclopentadiene yields hydroxycyclo-
pentene.29 Hydroxycyclopentenes, 15 years earlier, were
obtained from γ-allenic aldehydes by intramolecular heteroene
synthesis.30
a
Isolated yield after column chromatography (basic Al2O3, hexane,
b
CH3Cl). The reactions were carried out with acetylene 1a [initial
pressure at ambient temperature was 12−14 atm (stirred reactor)],
1,5-diketone 5 (6 mmol), KOH·0.5H2O (0.2 g, 3 mmol), DMSO (50
c
d
mL). The reaction time was 0.5 h. Diastereomers ratio = 4:1.
e
Acetylene 1b (7.7 mmol).
understood as a nucleophilic attack by hydroxide ion at the acyl
carbon resulting in displacement of the cyclopentenol anion
(Scheme 2). This scheme is supported by isolation of 4-
pyridinecarboxylic acids in 32% yield from the acidified reaction
mixture.
In the reaction of phenylacetylene 1b with 1,5-diketone 5b, the
formed cyclopentene 3h undergoes both deacylation and
dehydration to the corresponding cyclopentadiene 9h (Table
2, Scheme 3). The driving force of dehydration of the
intermediate cyclopentenol 4h is likely the formation of the
cyclopentadiene conjugated with two benzene rings.
It is obvious that, upon optimization, both deacylation and
dehydration can be implemented as one-pot procedures, directly
from acetylenes and ketones. Thus, this reaction opens an easy
one-step access from cheap available materials not only to
Despite the above advances in the synthesis of functionalized
cyclopentenes, their one-pot assembly from such available and
cheap starting materials as acetylenes and ketones under
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transition-metal-free conditions opens additional possibilities for
their synthetic and pharmaceutical applications.
Apparently, larger scale synthesis of cyclopentenes via this
reaction requires special optimization. Optimistically, our first
attempt to scale up the reaction using 10 g of ketone 2a gave a
42% yield of cyclopentene 3a thus implying applicability of the
reaction for large scale synthesis.
In conclusion, a facile one-pot diastereoselective assembly of
functionalized cyclopentenes from two molecules of acetylene
and two molecules of ketone in the presence of a KOH/DMSO
system has been discovered. The assembly involves four C−C
bond forming reactions in one synthetic operation. 1,5-
Diketones have been shown to be the key intermediates of the
reaction, and their condensation with acetylenes under similar
conditions to give the same cyclopentenes has been
implemented. These approaches allow cyclopentenes to be
synthesized in a yield up to 66%. In view of the high
pharmaceutical importance of the functionalized cyclopentenes,
this simple and conceptually new synthetic strategy may become
another route to cyclopentenes and a fresh contribution to both
acetylene and ketone chemistry.
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ASSOCIATED CONTENT
* Supporting Information
■
S
1
The experimental procedure, compound characterization, H
and 13C NMR spectra of all compounds, and crystallographic
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
(22) Parry, R. J.; Haridas, K. Tetrahedron Lett. 1990, 31, 7549.
(23) Luparia, M.; Vadala,
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A.; Zanoni, G.; Vidari, G. Org. Lett. 2006, 8,
*E-mail: boris_trofimov@irioch.irk.ru.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by a grant of Russian Scientific
Foundation (Project No. 14-13-00588).
■
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