Fe(III)-Catalyzed, Cyclizative Coupling between 2-Alkynylbenzoates and Carbinols: Rapid Generation of Polycyclic Isocoumarins and Phthalides and Mechanistic Study

Article abstract of DOI:10.1002/adsc.202000313

FeCl₃ catalyzed, highly regioselective cyclizative coupling of internal alkynes with alcohols has been reported for the rapid synthesis of structurally divergent, complex isocoumarins and phthalides respectively in intermolecular and intramolecular fashion. This strategy exhibited very high substrate scope and efficiency and proceeds through the simultaneous formation of C?O and C?C bonds. Observations from a series of control experiments supported a) the mechanism as Lewis acid catalyzed dual activation of ester and alcohol, b) the role of carbocation for the enhanced rates of cyclization, i. e., activation of alkyne by carbocation, and c) no role of HCl in the reported cascade process. (Figure presented.).

Full text of DOI:10.1002/adsc.202000313

Title: Fe(III)-catalysed, Cyclizative Coupling between 2-
Alkynylbenzoates and Carbinols. Rapid generation of Polycyclic
Isocoumarins and Phthalides and Mechanistic Study
Authors: Beeraiah Baire and Soniya Gandhi
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10.1002/adsc.202000313
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Fe(III)-Catalyzed,
Cyclizative
Coupling
between
2-
Alkynylbenzoates and Carbinols: Rapid generation of
Polycyclic Isocoumarins and Phthalides and Mechanistic Study
Soniya Gandhi[a] and Beeraiah Baire*[a]
a
Department of Chemistry, Institute of Technology Madras, Chennai-600036
Email: beeru@iitm.ac.in
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. FeCl3 catalyzed, highly regioselective cyclizative coupling of internal alkynes with alcohols has been
reported for the rapid synthesis of structurally divergent, complex isocoumarins and phthalides respectively in
intermolecular and intramolecular fashion. This strategy exhibited very high substrate scope and efficiency and
proceeds through the simultaneous formation of C–O and C-C bonds. Observations from a series of control experiments
supported a) the mechanism as Lewis acid catalyzed dual activation of ester and alcohol, b) the role of carbocation for
the enhanced rates of cyclization, i.e., activation of alkyne by carbocation, and c) no role of HCl in the reported cascade
process.
Keywords: Isocoumarins; Domino cyclizations; Phthalides; 2-alkynylbenzoates; Lewis acid catalysis
presence of Au(I)/Pd(II) catalytic systems for the
Introduction
synthesis of C-4-alkylated isocoumarins.[4c] Several,
Pd(II)-catalyzed bimolecular reactions with olefins
The electrophilic activation-nucleophilic addition via Heck-type oxidative coupling were also known.[4d-
4h]
based cascade processes of alkynes in presence of
Lewis acid catalysts continue to be a fascinating area
of research in organic synthesis. These strategies
provide simultaneous construction of multiple C-C,
C-O and C-N bonds, thereby an opportunity to build
the complexity in a rapid and efficient manner.[1] The
2-alkynylbenzoates and -alkynylenoates have been
well utilized as building blocks for the synthesis of
Scheme 1. Known methods for the C4-alkylated
isocoumarins from 2-alkynylbenzoates/alkynylenoates.
isocoumarins(pyrones)
as
well
as
phthalides(butenolides) under Lewis acid and
transition metal catalysis.[2] They have also been used
in the generation of C-4 functionalized isocoumarins
with non-carbon electrophilic trapping such as SR,
SeR, X etc.[3] In contrast, simultaneous creation of
isocoumarins followed by functionalization of C-4
position with carbon electrophiles has been less
explored in the literature.[4] The research groups of
Komeyama and Melen have reported a Lewis acid
[Bi(OTf)3 and B(C6F5)3 respectively] catalyzed
intramolecular migration of alkyl group from ester to
Nonetheless, to the best of our knowledge, the
cyclizatve coupling between the methyl 2-
alkynylbenzoates/-alkynylenoates and alcohols
either in an intramolecular or intermolecular fashion
is not reported so far.
In continuation of our interest in the exploration
of novel reactivity's of alkynes and propargylic
alcohol derivatives,[5],[6] here in we discovered and
developed a FeCl3 catalyzed, cascade cyclizative-
coupling process between methyl 2-alkynylbenzoates
(-alkynylenoates) and alcohols. This process can be
operational both in intermolecular and intramolecular
C-4 position of the isocoumarin (Scheme 1).[4a],[4b]
A
dual (co-operative) catalysis based intramolecular
migration of allyl group has also been reported, in
1
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10.1002/adsc.202000313
Advanced Synthesis & Catalysis
versions and provide access to structurally novel, efficiency (60%). We next performed the reaction in
complex 4-C-substituted isocoumarins (pyrones) as various solvents employing 5 mol% of FeCl3, and 1.3
well as phthalides (butenolides) under mild reaction equiv. of alcohol at 80 °C (entries 10-13). Both 1,2-
conditions. The design, discovery and development DCB and CH2Cl2 gave 85% and 82% respective
constitutes the current manuscript
yields of product 9a (entries 10 & 11). Whereas in
Recently we reported a FeCl3 promoted, formal CHCl3 and toluene (entries 12 & 13), reactions were
[3+2]annulation of diarylalkynes 1 and indole-3- slow (9 h and 24 h) and resulted in reduced yields
carbinols 2 for the synthesis of cyclopenta[b]indole 3 (68% & 51%) for 9a along with 20% and 30% of
(Scheme 2A). In continuation, when we employed a unreacted starting material 4, respectively.
diarylalkyne possessing an o-methyl carboxylate
Table 1. Optimization Study.
group 4, against the alcohol 5, a new product, an
isocoumarin 6 was isolated (34%) along with the 3-
vinylindole[7] 7 (14%) and its dimer 8 (10%). (Scheme
2B) Delighted by the fortuitous observation, we
aimed to pursue this transformation in systematic
manner.
Scheme 2. A) Coupling of indole-3-carbinols and alkynes
for cyclopenta[b]indoles (Earlier work); B) Discovery of
new mode of reactivity for substituted isocoumarins (This
work).
a 10%, b 30%, c 20%, d 20%, e 10%, f 20%, g 30% of 4, h
Results and Discussion
isolated yields
We started our investigation employing 2-
alkynylbenzoate 4 (possessing phenyl group on the
alkyne terminus) as a model substrate against
diphenylmethanol. Treatment of a mixture of 4 and
alcohol (1 equiv.) in 1,2-DCE with MsOH (20 mol%)
at 50 °C (entry 1, Table 1) gave the expected
isocoumarin 9a as the exclusive product, via a 6-
endo-dig cyclization–coupling cascade, in 68% yield
after 10 h. There was no detection of any traces of the
corresponding phthalide (via 5-exo-dig cyclization).
Employing other Brønsted acids (entries 2 & 3) such
as, pTSA (20 mol%) and TfOH (20 mol%) resulted in
poor yields (50% & 40%; 24 h & 2.5 h) of 9a
respectively. On the other hand, employing FeCl3 (20
mol%, entry 4,) gave 71% yield of 9a after 4 h at
50 °C along with 20% of the unreacted 4. Increasing
the temperature to 80 °C gave the improved yield
(75%) for 9a with shorter reaction time (1.5 h) along
with 20% of 4. Next increase in amount of alcohol
(1.3 equiv.) with FeCl3 (20 mol%) and at 80 °C (entry
6), further improved the yield of 9a to 82% with
complete consumption of 4. A gradual decrease in
amounts of FeCl3 to 10 mol% and 5 mol% (entries 7
& 8) resulted in 88% and 90% respective yields of 9a
after 1 h and 1.25 h, at 80 °C. Further decrease to 2
mol% (entry 9, Table 1) hampered the reaction
So the optimized condition for the discovered
bimolecular cyclizative coupling of 2-
alkynylbenzoates with alcohols is, alcohol (1.3
equiv.), FeCl3 (5 mol%), 1,2-DCE and 80 °C (entry 8,
Table 1). We next focused to evaluate the strength
and weakness of this methodology. Initially we
screened various alcohols against the 4 (Scheme 3).
Structurally divergent biaryl as well as aryl-alkyl
carbinols have been successfully employed under
standard reaction conditions to generate library of
novel isocoumarin derivatives 9b-h in excellent
yields (70-85%). In case of indole-3-carbinols, the
reactions were very fast, but yields of the coupled
products 9i-j, 6 were relatively poor (45-50%). We
also employed aryl-propargyl as well as aryl-allyl
alcohols. In both the cases, expected coupled
isocoumarins 9k (42%, NMR yield) and 9l (65%,
NMR yield) were isolated as inseparable mixture with
the simple isocoumarin 10, along with ~30% of ester
4. In addition to the spectroscopic data, the presence
of the coupled isocoumarin frame work has also been
unambiguously confirmed by the single crystal X-ray
diffraction analysis of the compound 6 (Scheme 3).[8]
2
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10.1002/adsc.202000313
Advanced Synthesis & Catalysis
Scheme 4 Screening bicyclic and aliphatic carbinols.
conditions: ester 4 (1 equiv.), FeCl3 (5 mol%), alcohol (2
equiv.), 1,2-DCE, RT, 24 h; a 60%; b 48%; c 45%; d 55% of
starting material 4
Subsequently, we have also studied the scope of
substituted aryl groups on alkyne of 2-
alkynylbenzoates 11-14 against various alcohols
(Scheme 5). All the substrates underwent a smooth
and highly efficient cyclizative-coupling to afford the
corresponding
structurally
divergent
3,4-
dialkylated(arylated) isocourmarin derivatives 15a-h.
During this study we did not observe any electronic as
well as positional effect of substituents present on the
arene. With the acyclic -alkynyl-enoates 16 & 17,
the reactions found to be relatively slow and even
after 48 h at 80 °C, variable amounts (30% and 10%
respectively) of enaotes 16 & 17 were recovered
along with the poly-substituted pyrenones 18a (50%)
and 18b (80%).
Scheme 3 Scope study for alcohols and ORTEP diagram
for compound 6; conditions: ester 4 (1 equiv.), FeCl3 (5
mol%), alcohol (1.3 equiv.), 1,2-DCE, 80 °C.
In continuation, various bicyclic benzylic
alcohols have also been employed as coupling
partners (Scheme 4). When the reactions were
performed with alcohols (2 equiv.) and the 2-
alkynylbenzoate 4, with 5 mol% of FeCl3, at RT[9]
resulted in the formation of expected coupled
isocoumarins 9m-p as exclusive products but the
conversions were poor even after 24 h. In all cases
variable amounts of unreacted benzoate 4 was
isolated. Further, dialkylcarbinols, primary alcohols
(allylic and benzylic), styrene and methyl acrylate
have also been employed as electrophilic carbon
partners for the cyclizative coupling reaction under
standard conditions. In all cases, except the benzylic
alcohol, there was only cyclization reaction observed
to give the corresponding simple isocoumarin 10 (65-
75% yields) after 72 h, and no traces of coupling
products were observed. In contrast benzyl alcohol
underwent the coupling reaction to give a (1:1.2)
inseparable mixture of the coupled isocoumarin 9q
and simple isocoumarin 10. It is noteworthy to
mention here that, all the above reactions (though
underwent simple cyclization) are very slow and took
about 72 h for the complete consumption of the
starting 2-alkynylbenzoate 4. This might suggests that,
the stable carbocationic intermediate (generated from
Lewis acid and alcohol) is necessary for the activation
of the alkyne to promote the efficient cyclization
process as well as coupling with enhanced reaction
rates.
Scheme 5 Diversity of alkyne substituent's and tethers.
Conditions: ester (1 equiv.), FeCl3 (5 mol%), alcohol (1.3
equiv.), 1,2-DCE, 80 °C.
Surprisingly, placing an alkyl group on the
alkyne terminus promoted a highly regio-selective 5-
exo-dig cyclization-coupling cascade to generate the
complex phthalide derivatives 19a-c in good yields
(Scheme 6). This might be due to the more stabilized
carbocationic (benzylic) character at the internal
3
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10.1002/adsc.202000313
Advanced Synthesis & Catalysis
acid 23 and alcohol through hydrolysis, whereas after
45 min, directly gave the expected product 9a in 85%
yield. On the other hand treatment of the mixture of
acid and alcohol with standard reaction conditions,
also gave the product 9a (90%). These observations
suggests that, a) there is no trans-ester formation
under reaction conditions, i.e., intramolecular alkyl
group migration,[4b] b) the reaction does not involve a
step wise C-O bond (isocoumarin formation)
carbon of the alkyne. In all cases a diastereomeric
(E/Z) mixture was isolated.
Scheme 6 Regioselectivity reversal with alkyl-substituents
on alkyne for the selective generation of 3-ylidene- followed by C-C bond formation (coupling) rather
phthalides
undergoes a simultaneous construction of both the C-
O as well as C-C bonds, and c) presence of alcohol,
To get some insights into the mechanistic details i.e., carbocationic species has influence on the rate of
of this cascade process, we performed several control the cyclization.
experiments (Scheme 7). To verify the possibility of a
trans-esterification followed by intramolecular alkyl
group migration, we treated the simple methyl
benzoate (lacks the alkyne at ortho- position) with the suitable mechanism for the discovered bimolecular
Based on these observations, we proposed a
diphenyl alcohol under standard reaction conditions
(eq. 1). The trans-esterification was not observed;
instead the corresponding ether 20 was isolated[10]
along with unreacted methyl benzoate. Next, we
subjected 4 to standard reaction conditions, but in the
absence of any of the alcohol partner (eq. 2). This
resulted in an exclusive formation of the simple
isocoumarin 10 (70%) with only 70% conversion of 4,
even after 24 h at 80 °C. No traces of the 4-methyl-
isocoumarin 21 was identified. The observed slower
reaction rate for the formation 10 again (compare with
Scheme 4) suggests the requirement for the possible
electrophilic activation of alkynes by the carbocation
intermediate (generated from alcohol), which lacks in
the absence of alcohol in the reaction mixture.
cyclizative coupling process (Scheme 8). Initial
activation of both alcohol and ester by the acid
generates carbocation species 24 and a zwitter ionic
species 25 (Scheme 8, eq. 5 & 6).[4b] Next activation
of the alkyne by electrophilic carbocation[11] 24 and 6-
endo-dig attack by the ester, followed by
demethylation by hydroxide ion gives the coupled-
isocoumarin 26. To verify the presence of HCl (if
any) under reaction conditions and its role in the
observed reactivity with alcohols, we performed the
reaction with diphenylmethyl chloride in place of
corresponding alcohol under anhydrous conditions
(Scheme 8, eq. 7). Here since no hydroxide is present,
no possibility for HCl formation under reaction
conditions. Delightfully, the reaction is clean and
gave the product 9a in 80% yield (eq. 7). This
observation rules out the presence as well as catalytic
role of HCl during the standard reaction conditions.
Scheme 8 Proposed mechanism and control experiment to
rule out the role of HCl
Scheme 7 Control experiments
After studying the bimolecular coupling of
methyl 2-alkynylbenzoates and -alkynylenoates with
alcohols and understanding the mechanistic details of
this process, we next planned to develop the
corresponding intramolecular version (Scheme 9) for
the generation of polycyclic systems via a domino,
Further, treatment of the isocoumarin 10 with
diphenyl alcohol, under standard reaction conditions
(eq. 3), failed to produce any of the coupled
isocoumarin 9a, instead the ether 20 was isolated
along with unreacted isocoumarin 10. We also
prepared a diphenyl carbinol ester 22, and subjected
to standard reaction conditions (eq. 4). Surprisingly,
after 5 min (workup with water), it gave a mixture of
4
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10.1002/adsc.202000313
Advanced Synthesis & Catalysis
double-cyclization strategy i.e., lactonization– the major. A single crystal X-ray diffraction analysis
intramolecular coupling.
of the major isomer of the compound 27aZ,
unambiguously confirmed the presence of the
chromene based phthalide framework.[12] Further, we
have employed substrates varying in the nature of
tethered aryl group and also acyclic substrates, i.e., Z-
enynoates for the generation of corresponding
polycyclic phthalides 27n-o and butenolides 27p-q in
good yields. Nitrogen tethered 2-alkynylbenzoate-
alcohols were also employed for the generation
tetrahydroquinoline based phthalides 27r-t (Scheme
9). Noteworthy to mention here that, in all three cases,
the Z- (27rZ-27tZ; major) and E-isomers (27rE-
27tE) were separable on column chromatography, in
contrast to their oxygen counterparts. A single crystal
X-ray diffraction analysis of the minor isomer of the
compound 27rE, unambiguously confirmed the
presence of the tetrahydro-quinoline based phthalide
framework.[13]
Scheme 10 Rationale for the observed E/Z-mixtures
The two stereoisomers across the exo-olefin, can
be formed either from two parallel trapping reactions
or they are inter-convertible under reaction conditions.
In order to verify and distinguish between these two
possibilities, a (1: 0.18; Z:E) mixture was heated at
various temperatures and observed no change in the
ratio. This observation suggests that, the two products
(Z- and E-isomers) may be forming during the
reaction via anti-and syn- trapping of the carbocation
respectively.
Scheme 9 a) Intramolecular domino-cyclizative coupling
of alkynes and alcohols; b) ORTEP diagrams for the
compounds 27aZ (major) and 27rE (minor).
Accordingly, various structurally divergent
methyl 2-alkynylbenzoates, possessing intramolecular
aryl carbinols tethered through an alkyl chain, have
been employed under standard reaction conditions.
Since the reactions found to be quicker and completed
in <5 min., we decreased the reaction temperature
from 80 °C to 50 °C for these intramolecular
substrates. All the substrates smoothly underwent the
cascade cyclization to generate the corresponding
phthalide based polycyclic hybrid structures 27a-m in
excellent yields (up to 98%) within 5-45 min at 50 °C.
Conclusion
In conclusion, a FeCl3 catalyzed, highly regioselective
cyclizative coupling of internal alkynes with alcohols
has been developed for the selective, rapid and
efficient synthesis of structurally divergent, complex
isocoumarins and phthalides. This process is operable
both in an intermolecular and intramolecular fashion
and involves the simultaneous construction of both
C–O and C-C bonds. This process exhibits a very
broad array of substrate scope with excellent yields.
Control experiments supported a) the mechanism as
Lewis acid catalyzed dual activation of ester and
In all cases an inseparable mixture of two
diastereomers (E- and Z-) across the newly generated
exo-olefin has been obtained, with the Z-isomer being
5
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10.1002/adsc.202000313
Advanced Synthesis & Catalysis
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alcohol, b) the role of carbocation for the enhanced
rates of cyclization, i.e., possible activation of alkyne
by carbocation, and c) no role of HCl in the reported
cascade process.
Experimental Section
General procedure for the synthesis of substituted
isocoumarin derivatives
To a solution of the ester (1 equiv.) in 1,2-dichloroethane
(1,2-DCE) (5 ml/0.21 mmol, 0.04 M), alcohol (1.3 equiv.)
under nitrogen atmosphere was added FeCl3 (0.05 equiv.).
The reaction tube was stirred at 80 °C in oil bath for 30
min-24 h. After completion of the reaction (by TLC
analysis), saturated NaHCO3 and CH2Cl2 were added to
reaction mixture and extracted with CH2Cl2. The crude
material was purified by column chromatography to yield
the corresponding isocoumarin derivatives.
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General procedure for the synthesis of phthalides
derivatives
To a solution of the hydroxy-ester (1 equiv.) in 1,2-
dichloroethane (3 ml/0.13 mmol, 0.04 M) under nitrogen
atmosphere was added FeCl3 (5 mol%). The reaction tube
was stirred at 55 °C for 5-30 min. After completion of the
reaction (by TLC analysis), saturated NaHCO3 and CH2Cl2
were added to reaction mixture and extracted with CH2Cl2.
The crude material was purified by flash column
chromatography to yield the corresponding phthalides
derivatives.
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We thank Indian Institute of Technology Madras, Chennai for
infrastructural facility. We thank SERB-INDIA, for financial
support through CRG/2019/000988. SG thanks IIT Madras for
HTRA fellowship
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information file.
7
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10.1002/adsc.202000313
Advanced Synthesis & Catalysis
FULL PAPER
Fe(III)-catalysed, Cyclizative Coupling
between
2-Alkynylbenzoates
and
Carbinols. Rapid generation of Polycyclic
Isocoumarins and Phthalides and
Mechanistic Study
Adv. Synth. Catal. Year, Volume, Page –
Page
Soniya Gandhi[a] and Beeraiah Baire*[a]
8
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