An Unusual Conversion of 2-(Alkynonyl)Alkynylbenzenes to Isocoumarins by a Retro-Favorskii-like Degradation

Article abstract of DOI:10.1002/asia.201900745

We report the discovery of an anomalous reaction of 2-(alkynonyl)alkynylbenzenes under Ag^I catalysis for the selective formation of isocoumarins. This reaction is previously undocumented for 2-(alkynonyl)alkynylbenzenes in terms of the reaction mechanism and the product formed. Water (H₂O¹⁸) labeling studies suggested a possible mechanistic pathway in which the initial formation of a pyrylium ion is followed by hydrative dealkynylation, that is, water incorporation and alkyne expulsion, similar to a retro-Favorskii reaction.

Full text of DOI:10.1002/asia.201900745

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Accepted Article
Title: An unusual conversion of 2-(alkynonyl)alkynylbenzenes to
isocoumarins via a retro-Favorskii reaction like degradation
Authors: Beeraiah Baire and Santhi Jampani
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Communication
An unusual conversion of 2-(alkynonyl)alkynylbenzenes to
isocoumarins via a retro-Favorskii reaction like degradation
Jampani Santhi[a] and Beeraiah Baire*[a]
Abstract: We report here the discovery of an anomalous reactivity
of 2-(alkynonyl)alkynylbenzenes under Ag(I) catalysis for the
selective formation of isocoumarins. This reactivity is unexampled
before for 2-(alkynonyl)alkynylbenzenes in terms of reaction
mechanism and the product formed. Water (H2O18) labelling studies
suggested the possible mechanistic pathway as an initial formation
of pyrylium ion followed by hydrative-dealkynylation i.e., water
incorporation and alkyne expulsion, resembling a retro-Favorskii
reaction.
Scheme 1 Known reactivity of 2-(alkynonyl)alkynylbenzenes via pyrylium ion
In case of Au-catalysis the pyrylium ion 4b will be opened by water
to form a 1,5-diketone 5, which will further undergo an intramolecular
1,4-addition to generate the naphthol 3.6b On the other hand, under
Ag-catalysis 4a will be trapped in a 1,4-fashion by ROH to provide
alkoxyallenyl-isochromene 2.6a To the best of our knowledge, no
other reactions of 1 have been reported via the intermediacy of the
pyrylium ion 4. Herein, we discovered and explored an
unprecedented reactivity of 2-(alkynonyl)alkynylbenzenes, for the
selective generation of structurally diversified isocoumarins under
Ag(I) catalysis (Scheme 2B) via a retro-Favorskii reaction like
mechanism.
Isocoumarin natural products are highly abundant in marine sponge,
bacteria, fungi, lichens, molds, liverworts and in higher plants (Figure
1).1 They exhibit immuno-modulatory, anti-allergic, anti-fungal and
anti-angiogenic activities.2 Many synthetic strategies have been
reported for the synthesis of this family of natural products.3,4,5
As part of our ongoing interest on the exploration of Ag(I) catalysis
for the novel functionalization of alkynes and propargylic alcohols,7
recently, we developed a carbonyl directed, regioselective hydration
of alkynes.7a Here we employed arylketone 6 as the assisting group
(Scheme 2A) for the regioselective synthesis of 1,4- and 1,5-
diketones 7a and 7b respectively. In continuation of extending this
idea for other carbonyl directing groups, we turned our attention to
study the reactivity of 2-(alkynonyl)alkynylbenzenes 1 under Ag(I)
catalysis.
Figure 1 Representative example of bioactive isocoumarin natural products
2-(Alkynonyl)alkynylbenzenes 1 have already been employed as
building blocks in the literature.6 Several transition metal [Au(I) and
Ag(I)] catalysed processes are known (Scheme 1), but in a very
limited direction. These reports discuss about the conversion of 2-
(alkynonyl)alkynylbenzenes 1 to either allenyl-isochromanes 2 or -
naphthol derivatives 3 via the corresponding pyrylium ions 4a and 4b.
Scheme 2 A) Previous report from our laboratory employing arylketones as
the directing group; B) Ag(I)-promoted unprecedented reactivity of 2-
(alkynonyl)alkynylbenzenes (This work)
Our investigation began with the reaction of a 2-(alkynonyl)alkynyl
benzene 8a with AgOTf (2 equiv.) in toluene at RT (entry 1, Table 1).
To our surprise a new compound, i.e., an isocoumarin 10a was
isolated in 28% yield,8 instead of the diketone 5' as observed earlier
with arylketones.7a Formation of the isocoumarin 10a can be
explained only via the expulsion of the alkyne present in the
alkynone part of 8a via a tetrahedral intermediate like 9 (see
Scheme 6 for mechanism and control experiment). Nonetheless,
pleased by this differential reactivity of 2-(alkynonyl)alkynylbenzene
in comparison with literature reactivity as well as with respect to their
aryl counterparts, we aimed to reveal the mechanistic pathway of
this abnormal process. Accordingly, a screening study to obtain an
optimized reaction conditions for better yield of 10a was performed.
[a]
Department of Chemistry
Indian Institute of Technology Madras, Chennai
Tamilnadu, INDIA-600036
Table 1 Reaction discovery and optimization study for the generation of
isocoumarins
E-mail: beeru@iitm.ac.in
Supporting information for this article is given via a link at the end of
the document.
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10.1002/asia.201900745
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the dihydro-artemidin 10m, an isocoumarin natural product in good
yield (61%). Cyclopropylalkyne (8n) gave the isocoumarin 10n in
poor yield (33%) along with
a complex product mixture as
anticipated. Further, we have also employed substrates 8o-q with
different arylalkynes (on the bottom part) under standard reaction
conditions (Scheme 3). All three substrates resulted in the formation
of corresponding naphthols 12a-c (66%, 41%, and 30% respectively)
as major products along with minor amounts of expected
isocoumarins 10o-q ( 23%, 9%, and 6% respectively). The naphthols
12a-c can be obtained via an intramolecular 1,4-addition of the
corresponding 1,5-diketone intermediates 12a'-c' as reported in the
literature.6b To unambiguously confirm the presence of an
isocoumarin framework, a single crystal X-ray diffraction analysis
study was performed for the compound 10c and its ORTEP diagram
is depicted in Figure 2.9
a18% of 11a was isolated. THF = tetrahydrofuran; all the yields are after
purification.
Decreasing the amount of AgOTf to 1 equiv. (entry 2) improved the
yield of the isocoumarin 10a to 67% after 15 min at RT. But further
decrease to 30 mol% (entry 3) resulted in the reduced yield of 10a.
This might be due to the fact that the expelling alkyne may be
binding to the Ag(I) and hence blocks its catalytic activity. The
reaction was quicker (5 min) at 50 °C (entry 4) with 1 equiv. of
AgOTf, but gave only 31% of 10a. On the other hand performing the
reaction at 0 °C to RT (entry 5) in toluene, improved the yield of 10a
to 74%. Change in the amount of AgOTf to 60 mol% at 0 °C to RT
gave the best yield of 79% of 10a within 2 h (entry 6). Further
decrease to 30 mol% did not show any improvement. Reaction was
very slow and low yielding for 10a with AgNO3 even with super
stoichiometric amount (2 equiv., entry 8). In case of Ag2CO3, a
mixture of two isomeric six and five membered lactones 10a and 11a
was observed in 27% and 18% respective yields. We next performed
the reaction in various solvents with 60 mol% of AgOTf. The reaction
was smooth in both THF and acetone (entries 10 & 11) to give the
isocoumarin 10a in 60% and 71% yields respectively, whereas it was
poor in dichloromethane (entry 12). It is noteworthy to mention here
that, none of the above cases the diketone 5' was detected. Hence,
an optimized condition for the formation of isocoumarins from the 2-
(alkynonyl)alkynylbenzenes is 60 mol% of AgOTf in toluene at 0 °C
to RT (entry 6, Table 1).
Though the discovered process seems to be synthetically not viable
for the preparation of isocoumarins, the diverse biological activities
associated with relatively simple structural framework has prompted
us to verify the generality of this transformation to synthesize
structurally novel isocoumarins. Initially, we performed a scope study
(Scheme 3) for various alkynes keeping the unsubstituted propynone
as the carbonyl group. Structurally diverse cyclic tertiary-propargylic
alcohols 8b-8f have been employed. In all the cases, the reaction
was smooth and afforded the corresponding isocoumarin products
10b-10f in good yields (63-74%). The cyclohexenyl, aryl-methyl and
biaryl-propargylic alcohols 8g-i were also found to undergo the
discovered unconventional reaction to provide the respective
isocoumarins 10g-i, in 60%, 67% and 54% yields. In all three cases,
an unidentifiable mixture of products was also associated along with
10g, 10h, and 10i. Benzyl ethers and tosylates 8j-l were also found
to be compatible under reaction conditions, and provided the
isocoumarin products 10j-l in good yields (up to 77%). Employing
hexyne as the alkyne component (8m) resulted in the formation of
Scheme 3 Scope study for diverse alkynes
Figure 2 ORTEP diagram for isocoumarin 10c
Further, a scope study for substituent's effect on the ynone moiety
was also investigated (Scheme 4). Initially a phenyl substituted
ynone, was tested against several alkynes (propargylic alcohols) to
understand the ease of the reaction. In case of gem-dimethyl- and
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cyclohexyl- propargylic alcohols 8r and 8s, the reaction was smooth
under standard reaction conditions to yield the isocoumarins 10a
(50%) and 10c (40%) in moderate yields after 4 h and 3 h
respectively, at RT (eq. 1 & 2). When the cyclopentyl-propargylic
alcohol 8t (eq. 3) was employed, a new product 13a was also
isolated in 16% yield along with the expected isocoumarin derivative
10b (31%) after 1.25 h. The new product 13a found to be an -
hydroxyketone, which can be generated from the ynone assisted,
regioselective hydration of the propargylic alcohol (similar to
arylketone assisted process, see Scheme 2A).2a In case of alkynone
with nBu i.e., 8u (keeping the gem-dimethylpropargylic alcohol
constant, eq. 4) also formation of both isocoumarin 10a and -
hydroxyketone 13b in 52% and 11% respective yields was observed.
From these experiments it is clear that, the internal alkynones can
also be suitable substrates for the formation of isocoumarins, but in
terms of atom economy terminal alkyne is highly preferred.
isocoumarin 14 (in both cases). On the other hand, the TMS/TMS
substrate 8x underwent smooth reaction to give 14 in 57% of yield.11
This observation of low efficient conversions of terminal alkynes in
comparison with the internal alkynes, suggests that, the internal
alkynes (in the bottom part) are preferred over the terminal ones for
this transformation. We have also performed the reaction in
presence of added nucleophile such as MeOH (10 equiv.).
Surprisingly, there was no MeOH incorporation observed,6a instead
the regular product isocoumarin 10a was isolated in 47% yield, after
2 h.
Scheme 5 Use of acetylene, TMS-acetylene based substrates and MeOH as
nucleophile
Finally, based on our understanding of the process, a possible
mechanism has been proposed (Scheme 6A). Activation of alkyne 1
by Ag(I) followed by the 6-endo-dig cyclization of carbonyl group,
results in the formation of a pyrylium ion 4a. This upon hydration at
the carbonyl carbon provides the cyclic hemiacetal 9, the tetrahedral
intermediate. This 9 can now undergo two competitive yet distinct
pathways. One is the opening of the cyclic acetal to give the
hydrated product, diketone 5, which will under reaction conditions
further involve an intramolecular 1,4-addition to give the
corresponding naphthol 3. Secondly, it 9 can also involve the
expulsion of the Ag-activated alkyne to generate the isocoumarin 10,
similar to the retro-Favorskii reaction like degradation.12 It is
noteworthy to mention here that, overall the water is acting as a
carbonyl oxygen source.12c
Scheme 4 A) Scope study for substituents on alkynones; All reaction times
indicate the complete consumption of starting materials.
In order to verify the intermediacy of the -hydroxyketones (if any)
for the formation of isocoumarins, we have subjected the isolated (-
hydroxyketones 13a and 13b to standard reaction conditions (eq. 5,
Scheme 4). None of these substrates gave either the corresponding
isocoumarins 10b and 10a or the naphthol derivatives (as in the
literature, Scheme 1). This observation clearly ruled out the
possibility of intermediacy of the -hydroxyketones for the formation
of isocoumarin and also their inefficiency to be converted into the
naphthols as observed in case of aryl substituents (Scheme 3,
substrates 8o-q to 12a-c). This may be due to the preferred
enolization in case of aryl substituents over the alkyl substituents.
Scheme 6 Possible mechanism
In order to support the proposed mechanism, an isotopic labelling
(H2O18) reaction was performed with substrate 8c to see the
incorporation of O18 if any during the formation of isocoumarin
(Scheme 6B). Accordingly, treatment of a toluene (anhydrous and
degassed) solution of 8c with AgOTf (60 mol%) and H2O18 (6 equiv.)
under complete anhydrous conditions (Ar-atmosphere), to our
delight, gave the isocoumarin 10c-O18 with O18 incorporation. The
structure was characterised (IR, NMR) and confirmed by mass
In the literature,10 it is observed that terminal alkynes and TMS-
protected alkynes exhibit inertness under Au and Ag catalysis. But
encouraged by the successful use of terminal alkynones for the
formation of isocoumarins, we next employed various TMS-alkynes
and terminal alkynes as alkyne partners (down side) in this reaction
(Scheme 5). The reactions of substrates 8v and 8w (with R1/R2:
H/TMS and H/H) were found to be complex and gave only ~15% of
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10.1002/asia.201900745
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spectroscopy (HRMS). Further, to confirm the position of O18 at
carbonyl, the isocoumarin 10c-O18 was dehydrated with POCl3 and
Et3N at 0 °C to give the expected olefin 15 with O18 (Scheme 6B).
This outcome strongly supported the proposed mechanism and the
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tetrahedral intermediate
formation.
9 (Scheme 6A) for the isocoumarin
In conclusion, we discovered and explored an anomalous reactivity
of 2-(alkynonyl)alkynylbenzenes in the presence of Ag(I) salts for the,
unconventional synthesis of isocoumarins. The reactivity described
in this manuscript for 2-(alkynonyl)alkynylbenzenes is unexampled
before in terms of the mechanism and the products obtained. This is
a mild strategy for the generation of biologically relevant, and
structurally divergent isocoumarin frameworks. The H2O18 labelling
experiment and isolation of the O18-isocoumarin supported the
proposed mechanitic pathway as the hydrative-dealkynylation,
resembling a retro-Favorskii reaction, via the initial pyrylium ion
intermediate.
[5]
Acknowledgements
This work was financially supported by SERB-DST, INDIA through
EMR/2016/000041 grant. JS thanks IIT Madras, INDIA for HTRA
fellowship. We thank Mr. Ramkumar for single crystal X-ray analysis.
Keywords: 2-(alkynonyl)alkynylbenzenes • hydration • retro-
Favorskii reaction • isocoumarins • dealkynylation
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Unidentifiable complex mixture of products was also isolated.
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the observed amounts of the product 14.
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Table of Contents
Synthetic methods
Jampani Santhi, and Beeraiah Baire*
Page No. – Page No.
An unusual conversion of 2-
(alkynonyl)alkynylbenzenes to
isocoumarins via a retro-Favorskii
reaction like degradation
Text for Table of Contents
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