C3-Thioester/-Ester Substituted Linear Dienones: A Pluripotent Molecular Platform for Diversification via Cascade Pericyclic Reactions

Article abstract of DOI:10.1002/adsc.202000362

Substituted oxabicyclo derivatives bearing two quaternary carbon centers and five contiguous stereocenters have been synthesized from C₃-thioester/-ester substituted dienones, a simple and linear pluripotent molecular platform. The conversion proceeds from neat reactants, possibly via a thermally-driven pericyclic cascade manifold involving sequential (E)-s-trans to (E)-s-cis isomerization, oxa-6π-electrocyclization, and intermolecular, regioselective [4π+2π] cycloaddition. The proposed mechanism has been substantiated by intermediate trapping experiments and DFT studies. Such dienones have also been exploited to effect stereoselective cross Diels-Alder cycloadditions with olefins and sequential Diels-Alder/retro-Diels-Alder reactions with activated alkynes. The reaction is greatly influenced by the substituent effect exerted by the C₃-thioester/-ester group. (Figure presented.).

Full text of DOI:10.1002/adsc.202000362

Title: C3-Thioester/-Ester Substituted Linear Dienones: A Pluripotent
Molecular Platform for Diversification via Cascade Pericyclic
Reactions
Authors: Abhijit Bankura, Sandip Naskar, Sabyasachi Roy Chowdhury,
Rajib Maity, Sabyashachi Mishra, and INDRAJIT DAS
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000362
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10.1002/adsc.202000362
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
C3-Thioester/-Ester Substituted Linear Dienones: A Pluripotent
Molecular Platform for Diversification via Cascade Pericyclic
Reactions
Abhijit Bankura,+a Sandip Naskar,+a Sabyasachi Roy Chowdhury,+b Rajib Maity,a
Sabyashachi Mishra,b,* and Indrajit Dasa,*
a
Organic and Medicinal Chemistry Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road,
Jadavpur, Kolkata 700 032, India; e-mail: indrajit@iicb.res.in
Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal 721 302, India; e-mail:
b
mishra@chem.iitkgp.ac.in
Equal contribution
+
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
found that the introduction of an ester group at the
C3-position of dienals dramatically altered the course
of the reaction due to the remarkable accelerating
effect of this substituent. For instance, dienals
Abstract. Substituted oxabicyclo derivatives bearing two
quaternary carbon centers and five contiguous stereocenters
have been synthesized from C3-thioester/-ester substituted
dienones, a simple and linear pluripotent molecular
platform. The conversion proceeds from neat reactants, underwent pericyclic rearrangement in refluxing
possibly via a thermally-driven pericyclic cascade manifold
toluene solution via [1,5]-H shift of the aldehyde
hydrogen to afford the intermediary vinyl ketene
intermediate which was subsequently captured by an
alcohol, olefin, or imine to afford esters,
cyclobutanones, or azacyclobutanones (Scheme 1).[4a]
They also succeeded in accelerating the key 6π-aza-
electrocyclization step for the synthesis of
multisubstituted piperidine and pyridine derivatives
from 1-azatrienes.[5a-g] The substituent effect was
rationalized based on molecular orbital calculation
which supports the contention that the substituent at
the C3-position of dienal reduces the activation
energy of the process.[5a,5c,5h]
involving sequential (E)-s-trans to (E)-s-cis isomerization,
oxa-6π-electrocyclization,
and
intermolecular,
regioselective [4π + 2π] cycloaddition. The proposed
mechanism has been substantiated by intermediate trapping
experiments and DFT studies. Such dienones have also
been exploited to effect stereoselective cross Diels-Alder
cycloadditions with olefins and sequential Diels-
Alder/retro-Diels-Alder reactions with activated alkynes.
The reaction is greatly influenced by the substituent effect
exerted by the C3-thioester/-ester group.
Keywords: Pericyclic reaction; dimerization; neat
reactants; cycloaddition; pluripotent molecular platform
Although substantial progress has been made with
the dienals, reagent-based cascade reactions of the
corresponding C3-carbonyl substituted dienones have
not been reported until recently due to the paucity of
methods available to access them.[6] Over the past
few years, we have been involved in the development
of synthetic methods for cyclopropanated furans,[6a]
regioselective E → Z isomerization of olefins,[6b] and
butenolides[6c-d] from dienones 1. Recently, we have
reported that neat 1 underwent dimerization due to a
substituent-driven acceleration effect via sequential s-
trans to s-cis isomerization/regioselective E/Z
isomerization/Diels−Alder cycloaddition to provide
cyclohexene derivatives 2 under direct excitation of
the reactant by visible light absorption (Scheme 1).[6b]
But dienones lacking such substitution did not
undergo the transformation (Scheme 1).
Introduction
Reagent-based diversity-oriented synthesis[1] that
utilizes a densely functionalized substrate (pluripotent
molecular platform) with cascade or domino reaction
sequences represents a powerful strategy in organic
synthesis and can immensely improve the efficiency
of a chemical reaction. In this strategy, a common
multifunctional substrate is transformed into diverse
topologically complex molecular frameworks by
using different reactants and reaction conditions.[2]
Several
well-designed
pluripotent
molecular
platforms have been developed by different research
groups.[1-3] Katsumura and Vanderwal’s groups have
extensively studied substituted dienals possessing
well-defined and dense array of interrelated
In the light of the above findings and to convert
densely functionalized dienones into diverse scaffolds,
functionalities.[4,5a-g] Katsumura
and co-workers
1
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10.1002/adsc.202000362
Advanced Synthesis & Catalysis
atom and step economical[8] transformation in
synthetic organic chemistry, enable a straightforward
access to complex and polycyclic products from
simple starting materials. Recently, Diels-Alder
dimerization of two identical 2H-pyrans has been
showcased as useful pericyclic cascade reactions,
which offer interesting applications in the biomimetic
synthesis of natural products.[7d-g] However, the
synthetic utility of monocyclic 2H-pyrans is
somewhat restricted due to the substrate-dependent
reversible nature of 6π-electrocyclization.[9] Increased
steric interactions and the presence of specific
electron-withdrawing groups in the π-conjugated
system shift the equilibrium towards the 2H-pyran
form.[10]
We now report solvent- and reagent-free,[11] atom-
and step-economical, regio- and stereoselective
thermally-driven cascade pericyclic reactions of
pluripotent dienones, which underwent dimerization
in neat condition, cross Diels-Alder cycloadditions
with olefins, and sequential Diels-Alder/retro-Diels-
Alder reactions with activated alkynes (Scheme 1).
Results and Discussion
The requisite dienones 1[12] were readily prepared in
pure form from the corresponding α-keto
thioesters[13a-d] or esters[13e-f] following our previous
reports. When 1a was kept at ambient temperature
o
(30 C), 3a was formed within a few days in 45%
yield along with 50% of the recovered starting
materials (Table 1, entry 1); the yellow crystalline
solid slowly turned to a light green gummy liquid
with the progress of the reaction. Extension of
reaction time led to higher conversion to the product,
o
while heating at 50 C accelerated the transformation
and improved the yield of 3a to 64% (entry 2),
although 1a was recovered to the extent of 15%. But
o
increasing the reaction temperature further (to 80 C)
proved counterproductive (entry 3). To improve the
reaction efficiency, different additives were tried
(Table 1, entries 4-9). But solid supports[14] such as
silica gel, zeolite, silver-exchanged zeolite,
montmorillonite
(surface
area
250
m2/g),
montmorillonite K 10 (surface area 220-270 m2/g),
Scheme
1.
C3-ester/-thioester
substituent-driven
and
ionic
liquids[15]
such
as
1-allyl-3-
1,3-
acceleration effect of dienals and dienones: previous and
present work.
methylimidazolium
dicyanamide,
dihydroxyimidazolium bis(trifluoromethylsulfonyl)-
imide all proved unsuccessful. It is noteworthy that
1a underwent decomposition in various solvents with
the formation of minor amount of 3a and substituted
butenolide derivatives (not shown).[6c-d]
We next assessed the substrate scope of this
dimerization reaction (Table 2). It was found that the
C3-thioester substituted dienones containing electron-
withdrawing or electron-donating substituents on the
C5-aromatic ring (1a-n) gave the expected products
3a-n bearing two quaternary carbon centers and five
contiguous stereocenters as single diastereomers in
moderate to good yields. Dienones containing phenyl
we planned to study their reactivity under thermal
conditions. It was anticipated that C3-C4 single bond
rotation of 1 would lead to the intermediate (E)-s-cis,
capable of adopting a conformation in which it can
undergo oxa-6π-electrocyclization to the reactive 2H-
pyran intermediate. This could be subsequently
trapped with a dienophile to deliver a range of
bridged bicyclic molecules (Scheme 1). The
anticipated product 3 was indeed isolated in minor
amount when dienone 1 was stored neat at ambient
temperature for a day. It may be pointed out that
pericyclic cascade reactions,[7] the most versatile
2
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10.1002/adsc.202000362
Advanced Synthesis & Catalysis
Table 1. Optimization studies for oxabicyclo derivatives.[a]
Table 2. Substrate scope for the C3-substituent-driven
rearrangement of dienones under thermal conditions.[a,b]
[a] Reaction conditions: 1a was kept at ambient temperature
or heated under the reaction conditions. Ambient
temperature: 30 oC.
[b] Unreacted starting materials 1a (for entry 1, 50%; entry
2, 15%; entry 5, 95%; entry 6, 16%; and entry 7, 92% )
were isolated.
[c] Unidentified inseperable mixtures were formed.
(OH)2Im-NTf2 = 1,3-dihydroxyimidazolium
bis(trifluoromethylsulfonyl)imide
and improved the yield of 3a to 64% (entry 2),
(1o), 3-thienyl (1p), or 1-naphthyl (1q) substituents at
the C-5 position also furnished the expected products
(3o-q). The replacement of the C5-aromatic ring with
an alkyl group like cyclohexyl was not tolerated (not
shown), perhaps due to the need for extended
conjugation for this pericyclic cascade reaction.
Further investigation demonstrated that C3-ester
substituted dienones (1r-y) containing C5-aromatic
ring, which proved more reactive than the thioester
analogous, could also be converted to the
corresponding products in moderate to good yields
(3r-y). But the expected product was not obtained
when a dienone (1z) bearing C3-COMe group was
o
either stirred at room temperature or heated at 40 C
o
to 50 C or higher temperature, possibly due to the
presence of an additional C3-keto group which leads
to undesired side reactions. Moreover, the
dimerization of substrates 1aa, 1ab, or 1ac[16] lacking
any substitution at the C3-position was completely
inhibited, which further supports the substituent-
driven acceleration effect caused by the C3-thioester/-
ester group.[17a]
[a] Reaction conditions: Neat 1 (0.1 g) was heated at 50 oC.
[b] Along with product 3, unreacted starting materials were
also isolated.
[c] Complex inseparable mixtures.
[d] Unreacted starting dienones (1) isolated.
We next sought to extend the scope of this reaction
by changing the C1-group (Table 2). Replacement of
the methyl group in dienone with an ethyl group
continued to afford the corresponding products
stereoselectively (3ad-3af), albeit a longer reaction
time was needed (60 h). In contrast, the substrate 1ag
endowed with a C1-phenyl group delivered the
product 3ag only in trace amount along with
decomposed materials.[17b] The expected product was
also not obtained when the C1-methyl group was
substituted with a hydrogen (1ah) or an ethoxy group
(1ai), attributed to the lack of sufficient electron
density on the C1-carbonyl group of dienones to
undergo subsequent oxa-6π-electrocyclization. The
structures of 3q and 3y were unambiguously
established by single crystal X-ray diffraction
analyses (Figure 1).[18]
A proposed mechanistic pathway for the
formation of 3 is shown in Scheme 2. We presume
that thermally induced (E)-s-trans to (E)-s-cis
3
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10.1002/adsc.202000362
Advanced Synthesis & Catalysis
intermolecular Diels-Alder cycloaddition of II with
dienone 1 would furnish the desired product 3.
We have quite recently reported that intermediate
I underwent dimerization under photochemical
conditions to yield 2 through an uphill E/Z
isomerization of C2-C3 double bond followed by a
Diels-Alder cycloaddition.[6b] In the present study
carried out under thermal conditions, we observed the
formation of dimerized product 3 exclusively.
Concerning the differences in reactivity between the
photochemical and thermal processes and subsequent
formation of the different dimerized products 2 and 3,
respectively, we presume that a barrier of 35 kcal/mol
(for 1o)[6b] between E and Z isomers proves to be too
large to be surmounted by the thermal events (at 50
oC reaction temperature), particularly in the absence
of any catalyst and solvent. Therefore, intermediate I
could not follow the E/Z isomerization pathway to
deliver 2 under thermal conditions (Scheme 2).
During our previous study under photochemical
conditions also, we had not detected/isolated any
dimerized product 3 arising from intermediate I.[6b]
This may be ascribed to the fact that photoabsorption
by the E-isomer excites the molecule to a higher
energy state from where the formation of Z-isomer
via the biradical mechanism may be a facile and
viable process than oxa-6π-electrocyclization;
subsequently the Z-isomer underwent rapid
dimerization to afford 2 as the only isolated
product.[6b] These results support the rationale behind
the isolation of dimerized products 2 (previous work)
and 3 (this work) exclusively under photochemical
and thermal conditions, respectively.
Figure 1. X-ray crystal structures of 3q (CCDC 1871161)
and 3y (CCDC 1871167). Thermal ellipsoids are shown in
50% probability level.
It is interesting to note that the dimerization
reactions summarized in Table 2 exhibit remarkable
regio- and diastereoselectivity, only one isomer being
formed in all cases.[19] Although several possible
dimerization pathways are possible after the
formation of 2H-pyran (step 2, Scheme 2), limited
degrees of freedom and restricted molecular motions
in the neat solid/liquid conditions of dienones may be
responsible for the excellent stereochemical result.
Moreover, we investigated the regioselectivity
associated with the Diels-Alder cycloaddition step
(step 3, Scheme 2) for the alternative products via
DFT calculations. It shows that the activation
energies associated with other regio- and
diastereomeric products are higher than those of the
experimentally observed product (see Figure S12 in
the Supporting Information for details).
The mechanism proposed in Scheme 2 is
corroborated by DFT calculations using substrates 1o
and 1y as the representative cases.[20a] It outlined the
reaction pathways by identifying the intermediates
and the transitions states. The activation energy
barriers for C3-C4 rotation of 1o and 1y to produce the
corresponding intermediate I are estimated to be 6.4
and 3.9 kcal/mol, respectively. As shown in Figure 2
and 3, the highest occupied molecular orbitals of the
trans- and cis- dienones have a very similar electron
density distribution delocalized over the conjugated
system. The antibonding overlap of the pz orbitals of
Scheme 2. Proposed mechanism for the formation of 3 and
results of DFT study of the reaction mechanism.
isomerization via C3-C4 single bond rotation could
lead to the corresponding intermediate I, which might
enable an oxa-6π-electrocyclic ring closure to afford
the intermediate 2H-pyran (II). Subsequent
4
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10.1002/adsc.202000362
Advanced Synthesis & Catalysis
C3-C4 seen in the HOMO of trans- and cis- isomers
shows a modified interaction in the transition state,
where the C2-C3 and C4-C5 double bonds are on
orthogonal planes and the antibonding overlap of C3-
C4 is quenched, leading to the stabilization of the
transition state, as reflected by the lower HOMO
energy in the transition state (Figure 2 and 3).[20a]
This makes the isomerization reaction facile. The
oxa-6π electrocyclization of intermediate I to produce
intermediate II is estimated to involve activation
energy barriers of 15.6 and 16.1 kcal/mol, for 1o and
1y, respectively. Finally, the Diels-Alder reaction of
the intermediate II with dienone 1 involves barriers
of 18.4 and 17.5 kcal/mol for 1o and 1y, respectively.
Taken together, the DFT calculations show a smaller
activation energy barrier for each step in the reaction
involving 1y as compared to 1o, thus explaining the
high reactivity of the former (Scheme 2). [20b-c]
Since we were unable to isolate the intermediates,
trapping experiments with nitrosobenzene as a
dienophile were conducted to better understand the
intermediacy of I/II in Scheme 2. When 1 was mixed
with 1.5 equiv of nitrosobenzene 4 and heated at 50
oC, two products each (5a/6a, 5b/6b, or 5c/6c) were
isolated (Scheme 3). Analysis of the product mixtures
revealed that the products 5a-c must have formed via
the intermediate I, whereas 6a-c originated from the
intermediate II. The structures of 5b and 6a were
unambiguously established by single crystal X-ray
diffraction analyses (Figure 4).[18]
Scheme 3. Intermediate trapping experiments with
nitrosobenzene 4 as a dienophile.
Figure 2. The HOMO and LUMO of trans- and cis-
isomers of 1o and those of the transition state separating
the two.
Figure 4. X-ray crystal structures of 5b (CCDC 1871168)
and 6a (CCDC 1871169). Thermal ellipsoids are shown in
50% probability level.
Once the suitability of the dienones 1 for
dimerization via pericyclic cascade rearrangement
was demonstrated, the feasibility of the significantly
more challenging cross Diels-Alder cycloadditions
with olefins was examined, since 1 underwent slow
dimerization even at ambient temperature (Scheme 4).
We observed that the desired hybrid cycloadducts 9a-
f and 10a-e were obtained exclusively as single
diastereomers in good yields with no trace of
dimerization product when neat 3-thioester
Figure 3. The HOMO and LUMO of trans- and cis-
isomers of 1y and those of the transition state separating
the two.
o
substituted dienones 1 were heated at 50 C with
excess 1H-indene 7 or styrenes 8. However, when 3-
5
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10.1002/adsc.202000362
Advanced Synthesis & Catalysis
ester substituted dienone 1r was independently
employed in these reactions with 7 and 8, 10-17% of
dimerization product (3r) was also isolated along
with the desired cycloadducts 9f and 10e, presumably
because of the increased reactivity of 1r. The
structures of 9f and 10c were unambiguously
established by single crystal X-ray diffraction
analyses (Figure 5).[18,21]
We next sought to extend the scope of this reaction
by replacing the alkyl group of an acetylenic diester
(11) with aromatic rings (Ph and C6H4-p-Me). But the
expected products were obtained only in trace
amounts along with the unreacted starting dienones
(not shown), though the exact reason is not very clear
at this moment. Moreover, alkynes such as
diphenylacetylene and phenylacetylene were found to
be completely inactive under the standard reaction
conditions. Efforts to address this limitation and
further optimization are presently ongoing in our
laboratory and the findings will be reported in due
course.
Scheme 4. Stereoselective cross Diels-Alder cycloaddi-
tions with 1H-indene 7 and styrenes 8.
Scheme 5. Synthesis of substituted benzene derivatives
from dienones.
Conclusion
In conclusion, we have demonstrated the use of
linear C3-thioester/-ester substituted dienones as
pluripotent molecular platforms for reagent-based
diversity-oriented synthetic strategies under thermal
conditions. The neat substrates undergo highly regio-
and stereocontrolled cascade pericyclic reactions due
to the substituent-driven acceleration effect to
produce oxabicyclo derivatives bearing two
quaternary carbon centers and five contiguous
stereocenters. The proposed mechanism has been
Figure 5. X-ray crystal structures of 9f (CCDC 1871179)
and 10c (CCDC 1871178). Thermal ellipsoids are shown
in 50% probability level.
To further highlight the potentiality of the
pluripotent dienones, we next explored their utility in
the synthesis of substituted aromatic rings by reacting
with activated electron-poor alkynes as dienophiles
(Scheme 5).[22] Indeed treatment of dienones 1i and
1n with acetylenedicarboxylate (11) in neat
corroborated
through
intermediate
trapping
experiments and DFT studies. The reactions of these
dienones with olefins and activated alkynes have
been shown to generate the corresponding cross-
Diels-Alder cycloadducts and substituted benzene
derivatives, respectively. Thus, through the use of
branching paradigm under thermal conditions, we
could generate a set of distinct and diverse molecular
frameworks.
o
conditions at 50 C afforded Diels-Alder adducts III
and IV. Intermediate III underwent subsequent retro-
Diels-Alder reaction to yield 12a-b as separable
major regioisomers in moderate yields, while in situ
MeCHO elimination from the intermediate IV
yielded minor product 13a-b.[21] The selectivity of the
reaction is high, affording 12a-b and 13a-b as 14:1
mixtures of isomeric benzene derivatives.
Experimental Section
6
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10.1002/adsc.202000362
Advanced Synthesis & Catalysis
General Procedure and Representative Examples
S-methyl
(1'R*,2'S*,5'R*)-5'-acetyl-4''-chloro-
1',2',5',6'-tetrahydro-[1,1':2',1''-terphenyl]-4'-
carbothioate 10a: Prepared according to the general
procedure discussed above: Rf = 0.3; eluent, EtOAc/n-
hexane (10%); white solid (0.034 g, 83%); mp 72–74 C.
General Procedure for the Synthesis of 3. C3-thioester/-
ester substituted neat (E)-s-trans dienones 1 (solid or
o
o
gummy liquid) were heated at 50 C. After completion of
1H NMR (400 MHz, CDCl3): δ = 7.28 (d, J = 5.2 Hz, 1 H),
7.11 - 7.12 (m, 3 H), 7.03 (d, J = 8.0 Hz, 2 H), 6.67 - 6.70
(m, 2 H), 6.50 (d, J = 8.4 Hz, 2 H), 4.06 (d, J = 7.6 Hz, 1
H), 3.82 (t, J = 5.6 Hz, 1 H), 3.31 (ddd, J = 2.4, 5.4, 13.5
Hz, 1 H), 2.35 (s, 3 H), 2.30 (s, 3 H), 2.17 - 2.26 (m, 1 H),
1.91 ppm (d, J = 14.0 Hz, 1 H); 13C{1H} NMR (100 MHz,
CDCl3): δ = 207.8, 193.1, 141.6, 141.4, 138.2, 135.5, 133.1,
131.3 (2 CH), 128.2 (2 CH), 128.0, 127.8 (2 CH), 126.8 (2
CH), 48.0, 47.0, 39.7, 28.9, 23.9 (CH2), 11.6 ppm; IR
(KBr): ṽmax = 3934, 2937, 1710, 1648, 1153, 1017 cm-1;
HRMS (ESI): m/z calcd for C22H21ClO2SNa [M + Na]+:
407.0849; found: 407.0850.
the reaction (TLC), the crude residue was purified by silica
gel column chromatography [230–400 mesh; eluent: ethyl
acetate/n-hexane] to obtain 3.
S,S-dimethyl
(1R*,3R*,4R*,7R*,8S*)-8-acetyl-3-(4-
chlorophenyl)-7-((E)-4-chlorostyryl)-1-methyl-2-
oxabicyclo[2.2.2]oct-5-ene-5,7-bis(carbothioate)
3a:
Prepared according to the general procedure discussed
above: Rf = 0.3; eluent, EtOAc/n-hexane (15%); light red
o
1
solid (0.064 g, 64%); mp 71–73 C. H NMR (400 MHz,
DMSO-d6): δ = 7.44 (d, J = 8.0 Hz, 2 H), 7.37 (d, J = 8.8
Hz, 2 H), 7.29 (d, J = 8.8 Hz, 2 H), 7.17 (d, J = 2.0 Hz, 1
H), 7.09 (d, J = 8.8 Hz, 2 H), 6.78 (d, J = 16.8 Hz, 1 H),
6.40 (d, J = 16.4 Hz, 1 H), 5.53 (s, 1 H), 3.69 (q, J = 2.4
Hz, 1 H), 3.34 (d, J = 2.0 Hz, 1 H), 2.32 (s, 3 H), 2.15 (s, 3
H), 2.14 (s, 3 H), 1.55 ppm (s, 3 H); 13C{1H} NMR (150
MHz, CDCl3): δ = 206.8, 201.5, 188.7, 142.6, 140.3, 139.8,
135.0, 134.4, 134.0, 132.9, 128.9 (2 CH), 128.2 (2 CH),
127.8 (2 CH), 127.1 (2 CH), 125.6, 77.3, 71.6, 64.8, 55.9,
38.8, 32.2, 21.0, 13.3, 11.3 ppm; IR (KBr): ṽmax = 1708,
1660, 1490, 1411, 1356, 1304, 1249, 1176, 1095, 1008,
820 cm-1; HRMS (ESI): m/z calcd for C28H26Cl2O4S2Na [M
+ Na]+: 583.0548; found: 583.0532.
General Procedure for the Synthesis of 12a-b and 13a-b.
In a sealed tube, 1i or 1n (0.07 g, 1.0 equiv) was heated at
o
50 C with acetylenic diesters (11a-b, 4.0 equiv) under
neat conditions for 46 - 48 h. After completion of the
reaction (TLC), the crude residue was purified by silica gel
column chromatography [230–400 mesh; eluent: ethyl
acetate/n-hexane] to obtain 12a-b. Two separable
regioisomers [12a-b/13a-b = 14:1] was formed which was
confirmed by the mixtures of 1H NMR spectra.
Dimethyl 3-methyl-5-((methylthio)carbonyl)phthalate
12a: Prepared according to the general procedure
discussed above: Rf = 0.3; eluent, EtOAc/n-hexane (10%);
white solid (0.048 g, 63% from 1i and 0.042 g, 58% from
1n); mp 86–88 C. H NMR (400 MHz, CDCl3): δ = 8.39
(d, J = 1.6 Hz, 1 H), 7.96 (d, J = 1.2 Hz, 1 H), 3.95 (s, 3 H),
3.91 (s, 3 H), 2.49 (s, 3 H), 2.39 ppm (s, 3 H); 13C{1H}
NMR (100 MHz, CDCl3): δ = 191.2, 169.0, 165.4, 139.4,
137.4, 136.6, 132.6, 128.4, 126.3, 52.9, 52.8, 19.2, 12.0
ppm; IR (KBr): ṽmax = 1726, 1656, 1310, 1266, 1082, 831,
788 cm-1; HRMS (ESI): m/z calcd for C13H14O5SNa [M +
Na]+: 305.0460; found: 305.0484.
Dimethyl
(1R*,3R*,4R*,7R*,8S*)-8-acetyl-3-(4-
chlorophenyl)-7-((E)-4-chlorostyryl)-1-methyl-2-
oxabicyclo[2.2.2]oct-5-ene-5,7-dicarboxylate
3r:
o
1
Prepared according to the general procedure discussed
above: Rf = 0.3; eluent, EtOAc/n-hexane (25%); white
o
1
solid (0.065 g, 65%); mp 73–75 C. H NMR (600 MHz,
DMSO-d6): δ = 7.48 (d, J = 7.8 Hz, 2 H), 7.39 (d, J = 8.4
Hz, 2 H), 7.32 (d, J = 7.8 Hz, 2 H), 7.22 (s, 1 H), 7.12 (d, J
= 7.8 Hz, 2 H), 6.52 (d, J = 16.8 Hz, 1 H), 6.31 (d, J = 16.8
Hz, 1 H), 5.66 (s, 1 H), 3.79 (s, 3 H), 3.64 (s, 1 H), 3.50 (s,
3 H), 3.32 (s, 1 H), 2.16 (s, 3 H), 1.59 ppm (s, 3 H);
13C{1H} NMR (150 MHz, CDCl3): δ = 208.1, 173.0, 163.8,
145.6, 140.3, 134.6, 134.3, 134.0, 132.8, 132.6, 128.9 (2
CH), 128.1 (2 CH), 127.7 (2 CH), 127.0 (2 CH), 126.6,
76.6, 71.6, 59.0, 54.4, 52.8, 52.0, 38.3, 31.8, 21.1 ppm; IR
(KBr): ṽmax = 1721, 1490, 1441, 1367, 1274, 1216, 1080,
814, 756 cm-1; HRMS (ESI): m/z calcd for C28H27Cl2O6 [M
+ H]+: 529.1184; found: 529.1201.
Acknowledgements
Financial support for this work was provided by DST-SERB
(EMR/2016/001720) and (EMR/2015/001890). A.B., S.N., R.M.,
and S.R.C. thank CSIR-India, UGC-India, and IIT-Kharagpur,
respectively for their fellowships. I.D. thanks Mr. Atish Ambure
for carrying out some preliminary works in this project. We are
especially grateful to Dr. Basudeb Achari, ex-scientist of CSIR-
IICB for insightful discussions. We are thankful to the CIF-
Division of CSIR-IICB for analytical support.
General Procedure for the Synthesis of 9a-f. In a sealed
o
tube, 1 (0.05 g, 1.0 equiv) was heated at 50 C with 1H-
indene (7, 4.0 equiv) under neat conditions for 24 – 44 h.
After completion of the reaction (TLC), the crude residue
was purified by silica gel column chromatography [230–
400 mesh; eluent: ethyl acetate/n-hexane] to obtain 9a-f.
S-methyl
(1R*,4S*,4aR*,9aS*)-1-acetyl-4-(4-
chlorophenyl)-4,4a,9,9a-tetrahydro-1H-fluorene-2-
carbothioate 9a: Prepared according to the general
procedure discussed above: Rf = 0.3; eluent, EtOAc/n-
hexane (6%); light yellow solid (0.053 g, 75%); mp 124–
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8
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10.1002/adsc.202000362
Advanced Synthesis & Catalysis
[17] a) In the absence of electron withdrawing substituent
at the C3 of dienones, the computed activation energy
barriers for C3-C4 single bond rotation, oxa-6π
electrocyclization, and Diels-Alder product formation
are estimated as 9.6, 17.8 and 26.2 kcal/mol,
respectively. These barriers are considerably higher
than those obtained for 3-oxoester (1y) and 3-thioester
(1o) substituted dienone. This explains the lack of
product formation in the absence of an electron
withdrawing group at the C3-position. For details and
the comparison of the activation energy barriers for the
reaction with and without electron withdrawing groups
at the C3 position, see Figure S11 in the supporting
information; b) 1ag did not undergo oxa-6π-
electrocyclization presumably due to the lack of
sufficient electron density on the carbonyl group. The
effect of a Ph group at the C1-position of dienone could
also be explained by activation energy parameter. For
details and the comparison of the free energy profiles
of the reaction, see Figure S10 in the Supporting
Information.
initial step, i.e., C3-C4 sigma bond rotation requires
higher activation energy (by 2.5 kcal) for the thioester
than the oxoester, and the product (3y) derived from the
oxoester is thermodynamically more stable than that
obtained from the thioester (3o). All these observations
allowed us to conclude that the reactivity of esters is
higher than the thioesters; c) In Scheme 2, the first and
second steps are unimolecular while the third step is
bimolecular. The activation energy of the second step
of Scheme 2 is obtained from the difference in the
optimized energy of the transition state (between
intermediate I and 2H-Pyran) and the intermediate I
(Scheme 2). The activation energy barrier for the third
step (a bimolecular Diels-Alder reaction) of Scheme 2
is obtained from the energy difference between the
optimized transition state of the Diels-Alder reaction
and the reactant of this reaction (i.e., one molecule of
2H-pyran and one molecule of (E)-s-trans (1)). To
represent the overall reaction in a single energy profile,
we equated the energy of 2H-Pyran obtained in the
second step to the energy of the system containing 2H-
Pyran and the reactant in the third step of the reaction
(Scheme 2).
[18] CCDC 1871161 (3q), 1871167 (3y), 1871168 (5b),
1871169 (6a), 1871179 (9f), 1871178 (10c) contain the
supplementary crystallographic data for this paper.
These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK; fax: +44 1223
336033.
[21] It is noteworthy that the reaction did not proceed as
expected in various solvents and mostly unreacted
starting materials with traces of desired products were
isolated.
[22] a) D. Tejedor, A. Díaz‐ Díaz, R. Diana‐ Rivero, S.
Delgado‐ Hernández, F. García‐ Tellado, Org. Lett.
2018, 20, 7987–7990; b) K. Afarinkia, V. Vinader, T. D.
Nelson, G. H. Posner, Tetrahedron 1992, 48, 9111–
9171.
[19] The formation of a single diastereomeric product 3
was confirmed by the analysis of the crude product by
LC-MS.
[20] a) The trans- and cis- isomers of dienones (1o and 1y)
and the transition states are optimized with DFT M06-
2X/6-31G** method. For details, see computational
details in the supporting information; b) The difference
in the activation energy barriers between the ester (1y)
and thioester (1o) for the Diels-Alder step is small (0.9
kcal/mol). This value may be within the margin of
experimental error. It should also be noted that the
9
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Advanced Synthesis & Catalysis
FULL PAPER
C3-Thioester/-Ester
Substituted
Linear
Dienones: A Pluripotent Molecular Platform for
Diversification via Cascade Pericyclic Reactions
Adv. Synth. Catal. Year, Volume, Page – Page
Abhijit Bankura, Sandip Naskar, Sabyasachi Roy
Chowdhury, Rajib Maity, Sabyashachi Mishra,*
and Indrajit Das*
10
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