Transition-metal-free oxidative cyclization reaction of enynals to access pyrane-2-one derivatives

Article abstract of DOI:10.1039/d1ob00726b

A novel and efficient metal-free C-H functionalization of enynals is developed to synthesize α-pyrone derivatives via the formation of two C-O bonds. In this project, K2S2O8 has been introduced as an efficient oxygen source and C-H functionalization agent in regioselective oxidative cyclization reaction with a relatively broad substrate scope.

Full text of DOI:10.1039/d1ob00726b

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Transition-metal-free oxidative cyclization
reaction of enynals to access pyrane-2-one
Cite this: DOI: 10.1039/d1ob00726b
derivatives†
a,b
Received 14th April 2021,
Accepted 20th April 2021
b
b
c
Farzaneh Ansari, Hormoz Khosravi,
Alireza Abbasi Kejani, Mahsa Armaghan,
c
b,d
a
DOI: 10.1039/d1ob00726b
Walter Frank, Saeed Balalaie
*
and Farnaz Jafarpour
*
rsc.li/obc
A novel and efficient metal-free C–H functionalization of enynals in situ formed hemiaminal moieties to the triple bonds and
is developed to synthesize α-pyrone derivatives via the formation oxidation in the presence of different metal catalytic systems
8
of two C–O bonds. In this project, K
2
S
2
O
8
has been introduced as (Scheme 1a, path b). Indeed, this reaction is another example
an efficient oxygen source and C–H functionalization agent in of a nucleophilic addition reaction on ortho–alkynylaryl aldi-
2
b
regioselective oxidative cyclization reaction with a relatively broad mines in which water reacts as a nucleophile.
substrate scope.
The universal application of enynals and related precursors in
the synthesis of various hetero- and carbocyclic compounds
makes them one of the most attractive families of organic
1
molecules. Yamamoto and co-workers were the first to use the
unique features of these structures and their applications in a
tandem nucleophilic addition reaction which leads to the
2
alkenyl ether products. In the last decade, enormous efforts
have been made to promote applications of enynals as a
3
reliable and beneficial precursor in the nucleophilic addition,
1
f,4
1g,5
carbene-transfer,
cycloadditions,
and C–H functionali-
6
zation reactions. Unfortunately, despite the comprehensive
use of C–H functionalization reactions in modern organic
chemistry, these methods are restricted to scarce examples on
enynals. In this context, cyclization of 2-cyclic acetal derivatives
of enynals have been reported, with the aim of aldehyde
moiety addition to the alkyne segments, via gold-catalyzed
7
hydride shift. This method provides a route to the C–H
functionalization of enynals in three steps to synthesize inde-
nones (Scheme 1a, path a). As another path for the C–H
functionalization of enynals, isoquinolone scaffolds have been
generated through an intramolecular 6-endo-dig addition of
a
School of Chemistry, College of Science, University of Tehran, Tehran 14155-6455,
Iran. E-mail: Jafarpur@khayam.ut.ac.ir
b
Peptide Chemistry Research Institute, K. N. Toosi University of Technology, P. O. Box
1
5875-4416, Tehran, Iran. E-mail: balalaie@kntu.ac.ir
c
Institut für Anorganische Chemie und Strukturchemie, Heinrich–Heine–Universität
Düsseldorf, Universitätsstraße 1, 40225 Düsseldorf, Germany
d
Medical Biology Research Center, Kermanshah University of Medical Sciences,
Kermanshah, Iran
†
Electronic supplementary information (ESI) available. CCDC2051315. For ESI
Scheme 1 (a) C–H functionalization of enynals. (b) Metal-free C–H
functionalization of aldehydes. (c) Oxidation of enynals. (d) Present
work.
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
d1ob00726b
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Besides, the Youn group developed an NHC-catalyzed oxi- ium persulfate (K
2
S
2
O
8
) and tetra-ethylammonium bromide
dative cyclization of o-alkynyl benzaldehydes to obtain phtha- (TEAB) have been introduced as an inexpensive and convenient
lides and isocoumarins in which the regioselectivity was couple to generating acyl radical spices in the intramolecular
1
2,17
altered by changing the substitutions of the alkyne moiety cyclization reactions,
the first reaction was carried out in
9
(Scheme 1a, path b).
the presence of K S O and TEAB in DCE at 120 °C under the
2
2 8
Based on these reports, the development of new regio- argon atmosphere (Table 1, entry 1). Surprisingly, oxidative
selective and transition metal-free strategies that lead to cyclization product 2a (instead of 5-endo-dig product) was
efficient and step-economical C–H functionalization reaction obtained with exclusive regioselectivity in 12% yield.
on enynal structures remains a significant challenge.
In the next step, the reaction was fulfilled in some other
In recent years, aldehyde C–H functionalization has been additives (also as phase-transfer catalysts), including TBAI,
considered one of the most important and practical atom econ- TBAB, and KBr. The best performance was obtained in the
omic strategies for C–C and C–heteroatom bond formations. presence of TBAB. After an extensive oxidant screening (TBHP,
4 2 2 8 2 2 8
Although reports around this field mostly were focused on oxone, BPO, mCPBA, (NH ) S O , and K S O ), as illustrated in
metal-catalyzed reactions, in some cases, efficient transition Table 1, persulfates showed more reactivity for lactonization.
10
2 2 8
metal-free methods were also reported. In this regard, we In particular, K S O was found to be the best choice to give 2a
reported a TBHP assisted radical reaction for the synthesis of in 82% yield (Table 1, entries 1–6). This result can be related
indenones through the cyclization of aromatic acyl radical inter- to better solubility of potassium salts in organic solvent per-
1
1
18
mediates with alkynes. In 2013, Glorius and co-workers estab- forming the efficient transformation. Subsequently, the reac-
lished a new method for the synthesis of fluorenones involving tion was performed in various solvents with different
the direct intramolecular coupling of aldehyde to phenyl group polarities. However, these solvents were less efficient than DCE
using K
2
S
2
O
8
1
as a radical initiator for acyl radical formation (see ESI, Table S2†). It is noteworthy that the reaction yield
2
(Scheme 1b). As a well-developed strategy in organic synthesis, decreases by decreasing temperature and replacing argon with
it seems that acyl radical intermediates can help to remove the air atmosphere. Therefore, the optimized conditions were
restrictions of enynal C–H functionalization. confirmed to be 1.0 equiv. of 2-(phenylethynyl)quinoline-3-car-
In our previous work, we developed oxidative oligocycliza- baldehyde 1a, 2.0 equiv. of K , and 1.0 equiv. of TBAB in
tion of enynals and enynones with molecular oxygen through DCE (0.2 M) at 120 °C (Table 1, entry 2).
2 2 8
S O
5
a
the radical cation chain oxidation mechanism (Scheme 1c).
As exhibited in Scheme 3, the scope and generality of the
Benzannulated oxygen-bridged seven-membered ring systems reaction have been examined with various substitutions on both
have been generated in the presence of O2 and K S O as alkyne and quinoline moiety in the optimized reaction con-
2
2 8
2 2 8
readily available oxidants. K S O reacted as a cooxidant to dition. Quinoline with the various substituents at the different
increase the yields of reaction in the air condition. In the positions on the phenyl ring (such as Me, Et, isopropyl, OMe,
present work, we exhibit a different oxidative cyclization reac- and even aryl) afforded the desired products 2a–2i in good to
tion of enynals in the presence of persulfate oxidant (K
2
S
2
O
8
)
excellent yields (77–87%). The substrate 1j containing tert-butyl
and quaternary ammonium salt (TBAB) affording pyran-2-one
derivatives (Scheme 1d). In addition to the synthetic perspec-
tive, pyran-2-one scaffolds are prevalent in natural and biologi-
a
1
3
Table 1 Optimization of the reaction conditions
cally active compounds, such as Thunberginol A,
1
4
15
16
γ-Rubromycin, Cephalosol, and Novobiocin (Scheme 2).
To examine our hypothesis, 2-(phenylethynyl) quinoline-3-
carbaldehyde 1a was used as a model substrate. Since potass-
b
Entry
Oxidant
Additive
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
K
K
K
K
K
2
2
2
2
2
S
S
S
S
S
2
2
2
2
2
O
O
O
O
O
8
8
8
8
8
TEAB
TBAB
TBAI
KBr
—
TBAB
TBAB
—
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
12
82
15
20
35 c
ND
30
ND
ND
72
—
Oxone
BPO
mCPBA
(NH
—
TBAB
—
10
1
)
4 2
S
O
2 8
1
TBHP
25
a
Reaction conditions: 1a (102.0 mg, 0.4 mmol), oxidant (2.0 equiv.),
additive (1.0 equiv.), DCE (2.0 ml), under Ar atmosphere, 120 °C and
b
3
6 h. Isolated yields, the diastereomer ratios (dr) were determined
1
Scheme 2 Representative naturally and biologically active pyran-2- using H-NMR and endo/exo is >19 : 1 in all cases (using vinylic hydro-
c
one.
gen peaks). ND = Not detected.
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Scheme 4 Control experiments.
cyclization product 2n represents carboxyl radical (or related
compounds) as the possible intermediates, leading to final
cyclization (Scheme 4, eqn (2) and (3)).
The experiment was carried out in the presence of
N-bromosuccinimide (NBS) as a convenient source of the
bromine radical in the reaction conditions; a product with a Br
substituent on the pyrone ring confirms the presence of the
vinyl radical intermediate in the reaction mixture, which was
trapped with NBS (Scheme 4, eqn (4)). This novel reaction of
enynals in the presence of NBS and K
our research group.
2 2 8
S O is being studied in
Based on the pieces of evidence mentioned above and pre-
1
9
Scheme 3 Scope of the reaction.
vious reports,
Scheme 5. Initially, K
n-Bu N) S O , producing the tetrabutylammonium sulfate
the plausible mechanism is depicted in
2 2 8
S O
reacts with TBAB to generate the
(
4
2 2 8
substituent on the phenylacetylene segment reacted favorably
and furnished the corresponding product 2j in 79%.
radical anions (SRA) and the bromine radical at high tempera-
tures. The in situ generated SRA reacts with enynal 1 to provide
the acyl radical I. Afterward, the bromine radical combinates
with acyl radical to generate acyl bromide II. The generated
attacks this acyl bromide to form intermediate III. The
resulting intermediate can release sulfur trioxide through con-
The starting material with aliphatic alkyne 1k also reacted
smoothly to give the desired cyclization product 2k in 62%
yield. Then, the cyclization reaction of 2-(phenylethynyl) nico-
tinaldehyde 1l was investigated under the optimal reaction
condition. The desired product 2l was obtained with 87%
efficiency. To further generalize the scope of the reaction, this
methodology was explored with 2-(phenylethynyl) benz-
aldehyde 1n and some of its analogs 1m–1p. In these cases, a
small amount of the 5-exo-dig products 2n–2p was observed,
which may be related to the absence of pyridine as an elec-
tron-deficient group; hence, the carbon–carbon triple bond is
not sufficiently polarized. This supposition was confirmed
when an electron-withdrawing group was used on the phenyl
ring of enynal, and only the 6-endo-dig product 2m was
obtained. For more confidence, the structure of 2a was con-
firmed with the single-crystal X-ray analysis.
−
HSO
4
To elucidate the reaction mechanism, we designed some
control experiments, as shown in Scheme 4. When the reaction
was exerted in the presence of TEMPO (known as a radical sca-
venger), the yields decreased sharply, suggesting that this reac-
tion involves radical intermediates (Scheme 4, eqn (1)).
Afterward, the reaction of 2-(phenylethynyl)benzoic acid has
been performed under the optimized conditions. The same Scheme 5 Plausible reaction mechanism.
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Fig. 1 Potential energy surfaces of the intramolecular cyclization of 2-(phenylethynyl)benzoic acid (all energies are in kcal mol−1).
certed cleavage of the S–O bond and Hydrogen transfer. The which avoids using expensive transition metal catalysts. This
intramolecular radical cyclization of the resulting compound strategy provides the α-pyrone derivatives in high to excellent
takes place to form 6-endo-dig 2 or 5-exo-dig 3 products, depen- yields. The key feature of this C–H functionalization is the
ding on which carbon of triple bond is attacked.
2 2 8
introduction of K S O as an efficient and straightforward
To investigate the mechanism of intramolecular cyclization oxygen source. In addition, DFT calculation shows that alkyne
of 2-alkynyl benzoic acid as a critical step in determining groups can be activated using the bromine radical species in
diastereoselectivity, we carried out a series of density functional the intramolecular nucleophilic addition reactions.
theory (DFT) studies at the UB3LYP/6-31G(d) level of theory
2
0
using the Gaussian 09 package (Fig. 1). 2-(phenylethynyl)
benzoic acid has been selected as the model for 2-alkynyl Conflicts of interest
benzoic acid intermediates. DFT calculation shows that carboxyl
−1
There are no conflicts to declare.
radical species (INT-CR) is unstable, about 12.6 kcal mol , and
−1
the SRA needs 19.5 kcal mol in case of addition to alkyne
moiety (TS-SRA). In contrast, bromine radical is more reactive
than SRA in case of addition to alkyne and just needs 3.7 and Acknowledgements
.5 kcal mol− to form INT2, which was probably trapped in
1
2
S. B thanks Alexander von Humboldt Foundation for the
linkage research Group Program. We thank the Iran National
Science Foundation (INSF, Grant No 97005171) for the finan-
cial support acknowledgments.
control experiment 3 (TS1-endo and TS1-exo, respectively). It
seems that in the next step, intramolecular proton transfer con-
trols the diastereoselectivity of the reaction. The intramolecular
proton transfer of INT2 is in favour of TS2-endo due to the
strain of 6 and 7 membered ring TS (TS2-endo and TS2-exo,
respectively). The resulting carboxyl radicals lead to barrier-less
Notes and references
5
-exo-trig cyclization (INT3-endo and INT4-exo). Eventually,
INT3-endo forms INT4-endo through an unprecedented 1,2-
oxygen shift as the major product of the reaction. This investi-
gation presents new reactivity of Br. as an alkyne activator.
1
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