A base-promoted tandem approach to bicyclic 8-membered ring ketones

Article abstract of DOI:10.1039/d0ob00618a

A base-promoted tandem route toward unprecedented bicyclic 8-membered ring ketones is reported. Under our approach, the targeted products are delivered in high yields from phenylacetylenes and 1,3-diketones. The method has a good scope and gives access to a complex structure that offers a wealth of opportunities for further functionalization.

Full text of DOI:10.1039/d0ob00618a

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DOI: 10.1039/D0OB00618A
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A Base-promoted Tandem Approach to Bicyclic 8-Membered Ring
Ketones.
Emerson E. F. dos Santos, a Gabriela F. P. de Souza, a Deborah A. Simoni a and Airton G. Salles, Jr a*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A base-promoted tandem route toward unprecedented bicyclic 8-
membered ring ketones is reported. Under our approach, the
targeted products are delivered in high yields from
phenylacetylenes and 1,3-diketones. The method has a good
scope and gives access to a complex structure that offers a wealth
of opportunities for further functionalization.
Medium-sized rings (7–12 members) are widely prevalent
structures in natural products.1 However, their scarcity in
marketed drug molecules2 supports the notion of how
challenging is the synthesis of such moieties. Therefore, there
is a great deal of interest in the development of simple and
general methods to access these rings.
Diverse strategies toward the synthesis of medium-sized
rings have been developed employing intramolecular
approaches.3 Nevertheless, these studies are focused on a
distinct ring-forming step and demands previous construction
of a framework susceptible to be cyclized, leading to labor-
intensive multistep procedures. Conversely, intermolecular
approaches capable of forming two bonds sequentially in one
step are far less common.4
In this context, bicyclic 8-membered ring ketones represent
a
formidable synthetic challenge. To the best of our
knowledge, only a few approaches to access this motif in a
single chemical operation with good atom economy have been
reported (Scheme 1): rhodium(I)-catalysed intramolecular
[6+2] cycloaddition of 2-vinylcyclobutanones and alkenes5a,
nickel-catalyzed intermolecular [4+2+2] annulation of
Scheme 1. Previous Work and Our Approach to Access Bicyclic
Eight-Membered Ring Ketones.
cyclobutanones
with
nonconjugated
diynes5b
and
photochemical approaches using UV irradiation5c and visible-
light irradiation5d. Formerly, in 1995, Dowd et al. reported a
free radical ring-expansion to access only one example of a
highly ionizing radiation and elaborated starting materials.
Therefore, alternative methodologies must be explored to
expand even more the organic synthesis toolkit.
Tandem cyclizations constitute an outstanding category of
one-pot reactions. These transformations are atom-
economical, highly efficient and waste-reducing owing to their
minimal work-up. Likewise, they are widely acknowledged as a
class of efficient reactions for the construction of polycyclic
bicyclic 8-membered
ring
ketone using organotin5e.
However, such methodologies are restricted to the use of
transition metal - based catalysts , toxic stannane reagents,
a. Department of Organic Chemistry, Institute of Chemistry, University of Campinas,
P.O. Box 6154, Campinas, São Paulo, 13084-862, Brazil.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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compounds.6 All in all, this approach might be a convenient Table 1. Optimization of the reaction conditionsa
candidate for the construction of medium-sized rings.
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DOI: 10.1039/D0OB00618A
Herein, we report the successful realization of a tandem
process of multiple bond-forming reactions that furnishes
unprecedented bicyclic furan/8-membered ring ketones. By
employing our method, we were capable to make use of cheap
and commercial chemical feedstocks (phenylacetylenes and
diketones) to obtain a range of products in high to moderate
yields. The rigidity of these fused motifs might be of great
relevance in medicinal chemistry functioning as drug
backbones.7a Furthermore, bicyclic 8-membered rings can be
found in biologically active molecules as Protosappanin A (anti-
inflammatory)7b, Marlignans (anti-HIV-1)7c and Arugosin F
(antifungal)7d.
O
O
M2CO3, CuI
O
+
DMSO, T
12 h
O
1a
3a
2a
Entry
1a
2a
CuI
M2CO3
(1.4
Equiv.)
T (oC)
Solvent
Yield
(%)b
(mmol) (mmol) (mol%)
1
2
3
4
5
0.5
1
1
1
1
0.5
0.5
0.5
0.5
0.5
12
12
12
12
12
K2CO3
K2CO3
Cs2CO3
-
100
100
100
100
140
DMSO
DMSO
DMSO
DMSO
DMSO
27
51c
58c
0
Our initial attempt began with the reaction of
phenylacetylene 1a (1 equiv.) and 1,3-diketone 2a (1 equiv.) in
the presence of CuI as a catalyst (12 mol%) and K2CO3 (1.4
K2CO3
91
(95)d
70
30e
0
6
7
8
9
10
1
1
1
1
1
0.5
0.5
0.5
0.5
0.5
5
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
140
140
DMSO
DMSO
o
equiv.) in DMSO at 100 C for 12 h. To our delight, the bicyclic
12
12
12
12
8-membered ring ketone 3a was obtained in 27% yield as the
only product and the starting materials were recovered
unreacted. (Table 1, entry 1). We unambiguously determined
its structure by single crystal X-ray diffraction (Figure 1).8
Ketone 3a captivated our attention because of its structural
novelty as a furan ring is formed along with the 8-membered
ring ketone. As far as we know this is an unprecedented
structure combining two interesting motifs. Encouraged by this
result, we conducted further optimization experiments (Table
1). The use of 2 equiv. of phenylacetylene 1a under O2
atmosphere proved to be beneficial to the reaction (entry 2).
Changing the nature of the carbonate counterion led to a
similar yield (entry 3). Nevertheless, the presence of the base
showed to be of paramount importance; otherwise, the
reaction is completely turned off (entry 4). The major advance
was made by changing the temperature of the reaction
medium (entry 5). Decreasing the amount of CuI to 5 mol% led
to a lower yield (entry 6) whereas shorter reaction times had a
negative impact on the transformation (entry 7). Finally, we
screened different solvents under reflux and all of them led to
inferior results.
Reflux Water
Reflux DMF
Reflux MeCN
60
0
a General conditions: 2.0 mL of DMSO and sequentially, 1a, 2a, M2CO3. b Yield of
c
d
isolated product.
Under O2 atmosphere.
Also under O2 atmosphere.
Conversion is given in parentheses (determined by 1H NMR). e 5 h reaction time.
be competent substrates in this transformation, furnishing the
corresponding bicyclic ketones in good to excellent isolated
yields (Scheme 2, 3a−3c). The exceptional success of fluorine-
containing drugs has been stimulating research on this
element in medicinal chemistry for drug discovery. The
incorporation of fluorine-atom(s) or fluorinated group(s) very
often provides molecules with quite unique biological
properties that cannot be achieved using any other element.9
Having this in mind, we tested 1-ethynyl-4-fluorobenzene in
this transformation along with 5-substituted diketones. The
corresponding bicyclic ketones were obtained in good to
excellent yields (Scheme 2, 3d−3f). Also, the reactions
employing
1-ethynyl-4-(trifluoromethyl)benzene
were
successfully accomplished giving the products in high yields
(Scheme 2, 3g, 3h). The reactions employing 1-ethynyl-4-
methylbenzene were effectively performed in good yields
(Scheme 2, 3i−3k). Next, we investigated the influence of the
substituent position on the phenylacetylene ring. Employing 1-
ethynyl-3-methylbenzene and 1-ethynyl-2-methylbenzene, we
obtained the desired products in high yields, suggesting no
effect of the substituent position whatsoever (Scheme 2,
3l−3n). An electron-donating substituent on the aryl moiety of
phenylacetylene was also tolerated in this transformation;
however, we obtained the corresponding product in lower
Having the optimized conditions in hand, we then explored
the substrate scope of the transformation using a range of
substituted phenylacetylenes and 1,3-diketones (Scheme 2).
Employing phenylacetylene 1a, we tested different 5-
substituted diketones and all of them were found to
yield (Scheme 2, 3o).
A
five-membered diketone
(cyclopentane-1,3-dione) in the presence of phenylacetylene
was also investigated under our conditions and did not lead to
the corresponding product. Such piece of information gave us
a clue about the mechanism of the transformation (vide infra).
Figure 1. Molecular structure of 3a with C and O atom labels
and 50% probability displacement ellipsoids.
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Scheme 3. Studies on the mechanism.
Next, we carried out a series of experiments to gain
mechanistic insight into the reaction. In order to obtain a
kinetic profile and detect any potential intermediates in this
transformation, we ran the optimized reaction employing 1a
and 2a taking aliquots at different time intervals and analyzing
the reaction composition. The GC-MS of the crude reaction
mixture after 1 h displayed a peak relative to the product 3a
along with the peak of 1,4-diphenylbuta-1,3-diyne and the
peak of phenylacetylene 1a (Scheme 3, item 1, also see Figure
S1 in the supporting information). After 3 h, the concentration
of 1,4-diphenylbuta-1,3-diyne reached its maximum whereas
product 3a and phenylacetylene 1a were present in a lower
concentration. We then noticed a gradual disappearance of
the peak relative to 1,4-diphenylbuta-1,3-diyne over time with
a concomitant increase in the intensity of the peak relative to
the product 3a. It suggests the 1,3-diyne as a potential
intermediate in this transformation. To assess this hypothesis,
we subjected 1,4-diphenylbuta-1,3-diyne and 1,3-diketone 2a
to the reaction employing only K2CO3 in DMSO, in absence of
O2 balloon, at 140 oC to check if product 3a could be obtained
Scheme 2. Scope of the Transformation. General conditions:
2.0 mL of DMSO, 1 (1 mmol). 2 (0.5 mmol), K2CO3 (1.4 mmol),
140 oC, O2 atmosphere, 12h. Yields of isolated products.
Knowing that two molecules of phenylacetylene engage in
this transformation, we also investigated combinations of
substituted phenylacetylenes. In this way, we could obtain
products with different substituents on the phenyl rings and
structurally richer. Unfortunately, a complex mixture of
compounds was obtained. In this scenario, purification was
unpractical and it hampered the use of such approach.
Likewise, aliphatic alkynes were tested and failed to furnish
any identifiable product. Again, a complex mixture was
observed under these conditions.
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(Scheme 3, item 2, see the Supporting Information for further
details). After 12 h, 3a was observed, thus confirming our
supposition and also demonstrating that copper and oxygen
does not participate in the step leading to product 3a. We did
not detect any other intermediate by GC-MS or NMR. The
Glaser coupling10 of phenylacetylene 1a in the presence of
copper would be the operative pathway to 1,4-diphenylbuta-
1,3-diyne which then undergoes the next step(s) leading to
product 3a. We then performed the reaction employing 1,4-
diphenylbuta-1,3-diyne and 1,3-diketone 2a in the presence of
TEMPO ((2,2,6,6- tetramethyl-piperidin-1-yl)oxyl) as a radical
scavenger. The formation of the ketone 3a was not inhibited in
this condition, thus ruling out the operation of a radical
pathway (Scheme 3, item 3; see the Supporting Information
for further details). We also tested an acyclic 1,3-diketone
(pentane-2,4-dione) as a substrate in this transformation
(Scheme 3, item 4) in order to inquire about the influence of
rigidity of the ketone on the mechanism. Interestingly, no
reaction took place and we isolated the self-condensation
product of pentane-2,4-dione and 1,4-diphenylbuta-1,3-diyne.
On the basis of the above evidence and reports in the
literature, we present a feasible mechanistic scenario for the
transformation depicted in Scheme 4. Deprotonation of the
1,3-diketone in the presence of K2CO3 gives access to the
corresponding enolate. We then hypothesized that the enolate
of 1,3-diketone add to the triple bond of the 1,3-diyne coming
from phenylacetylene (via Glaser coupling) to furnish the
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DOI: 10.1039/D0OB00618A
Scheme 4. Proposed reaction mechanism.
Conclusions
Overall, we have presented the preparation of bicyclic
furan/8-membered ring ketones via a tandem transformation
using K2CO3 as a base from phenylacetylenes and 1,3-
diketones. The method allows the preparation of
unprecedented bicyclic compounds. Phenylacetylenes bearing
different substituents were suitable substrates in this
transformation. Different 5-substituted 1,3-diketones were
also found to be competent substrates under our protocol. At
the moment, studies are ongoing in our group in order to
expand the scope of this reaction to use different
phenylacetylenes in the same transformation. Considering the
reactive sites of these bicyclic ketones, we anticipate that
additional transformations might be performed to
conveniently increase even more the structural complexity of
the products.
intermediate
A
(Scheme 4).11 Intramolecular [2+2]
cycloaddition would lead to cyclobutene B. In this scenario, we
assumed that the rigidity of a cyclic 1,3-diketone might play a
pivotal role placing the double bond and the triple bond of
intermediate A in close proximity to favor a possible
cycloaddition. Finally, cyclobutene B undergoes ring opening
to furnish the corresponding 8-membered ring ketone.12 The
driving force of this step would be the loss of steric strain and
the appearance of an extended conjugated chain.
As shown in Scheme 2, the transformation is more
favorable
for
electron-neutral
and
electron-poor
phenylacetylenes and, consequently, for the corresponding
diynes (compare 3a3n with 3o). Under our mechanistic
proposition, it suggests that the enolate addition to the diyne
leading to intermediate A has an important role in the overall
reaction rate. We hypothesize that the electron deficiency of
these dyines makes the enolate addition more favorable and
accounts for the higher yields of 3a3n. The steric influence of
the substituents on the diyne rings is not so noticeable
(compare 3i, 3l and 3n) probably because of the flat nature of
the diyne and the possibility of placing substituents on the
rings away from the enolate during its addition. On the other
hand, the size of the diketone ring seems to have a huge
impact on the transformation. According to our mechanism,
intermediate B has a tricyclic framework that would be
favored by the presence of a six-membered ring. As mentioned
above, the use of a five-membered ring diketone failed in this
transformation and it possibly can be linked to the extra
tension brought to the tricyclic framework by a five-membered
ring.
Conflicts of interest
“There are no conflicts to declare”.
Acknowledgements
We thank Fundação de Amparo à Pesquisa do Estado de São
Paulo (FAPESP, São Paulo, Brazil) for financial support (Grant
FAPESP 2017/18400-6). This study was financed in part by the
Coordenação de Aperfeiçoamento de Pessoal de Nível
Superior - Brasil (CAPES) - Finance Code 001.
Notes and references
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A base-promoted tandem route toward unprecedented bicyclic furan/8-membered ring
ketones is reported.