Silver triflate/: P -TSA co-catalysed synthesis of 3-substituted isocoumarins from 2-alkynylbenzoates

Article abstract of DOI:10.1039/c8ob00436f

In this paper, we describe the silver triflate/p-toluenesulfonic acid co-catalysed synthesis of seventeen isocoumarins and two thieno[2,3-c]pyran-7-ones starting from 2-alkynylbenzoates and 3-alkynylthiophene-2-carboxylates, respectively. The reaction proceeds with absolute regioselectivity under mild reaction conditions and low catalyst loading, to afford the desired products in good to excellent yields. A conceivable reaction mechanism is proposed and supported by isotope-exchange tests, ¹H NMR studies and ad hoc experiments.

Full text of DOI:10.1039/c8ob00436f

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Silver Triflate/p-TSA Co-Catalysed Synthesis of 3-SubsDtOitI:u10t.10e3d9/C8OB00436F
Isocoumarins from 2-Alkynylbenzoates
Jonathan Gianni, Valentina Pirovano, Giorgio Abbiati*
Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Generale e Organica “Alessandro
Marchesini”, Università degli Studi di Milano, Via Venezian, 21 – 20133 Milano – Italy
Corresponding author: giorgio.abbiati@unimi.it
ABSTRACT: In this paper, we describe the silver triflate/p-toluensulfonic acid co-catalysed
synthesis of fifteen isocoumarins and two thieno[2,3-c]pyran-7-ones starting from 2-
alkynylbenzoates and 3-alkynylthiophene-2-carboxylates, respectively. The reactions proceed with
absolute regioselectivity under mild reaction conditions and low catalyst loading, to give the desired
products in good to excellent yields. A conceivable reaction mechanism is proposed and supported
by isotope-exchange tests, 1H NMR studies and ad-hoc experiments.
INTRODUCTION
Isocoumarin nucleus1 is the core of numerous biologically active molecules.2 The most abundant
category of naturally occurring isocoumarins is characterized by the presence of a carbo-substituent
in 3-position. Great efforts have been devoted to the synthesis of isocoumarins both by metal-free3 or
metal-catalysed4 approaches. In this regard, the d-block of the periodic table have been widely
browsed: titanium, chromium, iron, ruthenium, rhodium, iridium, nickel, palladium, copper, silver,
gold, and zinc salts or complexes have been exploited as catalysts for the synthesis of these
heterocycles, although palladium and copper based catalysts remain the most studied and used among
all the transition metals.5
A possible synthetic strategy to build the pyran-2-one moiety of isocoumarin nucleus involves the
cyclization of -alkynyl carboxylic acids or esters under metal free conditions.6 One of the main
problem of these reactions is the regioselectivity, i.e. 6-endo-dig vs 5-exo-dig cyclization mode. In
2006 Uchiyama investigated the relationship between regioselectivity and acidic or alkaline reaction
conditions, by analysing in depth a model reaction. Whereas a basic environment favoured the 5-exo-
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dig cyclization mode, the formation of the pyran-2-one ring was selectively obtained aDtOrtI: u10s.1i0n3g9/Cst8rOoBn00g436F
acids as solvents or in refluxing toluene in the presence of catalytic amounts of acid.6a Alami6b,c
widened the scope for the synthesis of isocoumarins by a microwave-assisted cyclization reaction of
2-alkynylbenzoic esters in ethanol at 160 °C in the presence of 20-30 mol% of p-toluenesulfonic acid.
Some interesting examples of this kind of metal free approaches require the presence of an additional
electrophile.7 Beside the seminal works on electrophilic lactonization reported by Biagetti and Rossi
in 20027a and Larock in 2003,7b among the most recent papers are worth noting the iodolactonization
in ionic liquids reported by Mancuso and Gabriele7c and the oxoborilation of 2-alkynylbenzoic esters
published by Blum,7d yielding the corresponding 4-iodo and 4-borylated isocoumarins, respectively.
Moreover, the cyclization of -alkynyl carboxylic acids or esters have been also investigated under
Lewis acid or transition metal catalysis.8 In some cases, an inter/intramolecular electrophile is
introduced in the position 4 of the isocoumarin nucleus. One of the earliest interesting example of
that was reported by Zeni in 2011.8a A series of 4-Se, Te, S substituted isochromenones were
synthesized by cyclization of o-alkynyl benzoic esters at rt in the presence of 1 equiv. of FeCl3 and
different diorganyl dichalcogenides. Interestingly, in the absence of diorganyl dichalcogenide, the
corresponding 4 unsubstituted-isocoumarins were selectively obtained in good yields. One year later
Hashmi8d studied the gold catalysed conversion of 2-alkynylbenzoic esters into the corresponding
isocoumarin using in situ-generated Au(I) triflate (5 mol%). In these reactions, the allyl alcoholic
moiety of the ester can act as intramolecular electrophile. A more recent study on regioselective
gold(I)-catalyzed synthesis of 8-hydroxy-3-substituted isocoumarins from 2,2-dimethyl-5-(alkynyl)-
4H-benzo[d]-[1,3]dioxin-4-ones has been described by Mohapatra.8c Regarding Pd catalysis, a
cascade cyclization/oxidative olefination of tert-butyl 2-alkynylbenozates was reported in 2012 by
Han and Li,8d whereas inter- and intra-molecular cascade cyclohexane/addition of methyl vinyl
ketone8e or alkyne-tethered carbonyls8f have been studied by Lu and Han. More expensive metal
catalysts, such as Re,8g have been also recently tested.
In the latter years, some synthesis of isocoumarins have been also described directly starting from o-
halobenzoic acid/esters and terminal alkynes by means of domino coupling/annulation sequences.9
The more recent reactions are generally catalysed by copper-based catalysts (10-20 mol%), require
the presence of a base and heating9b,d or ultrasound activation.9c A further improvement of these
domino approaches is represented by the direct CH bond-activation/annulation sequence starting
from benzoic acids and internal alkynes, so yielding 3,4-disubstituted isocoumarins.10 For these
purposes expensive Ru,10a,b Ir10c catalyst were employed (2.5-10 mol%). Very recently, a similar Pd
catalysed approach that involves bromoalkynes as reaction partner, so allowing the formation of 4-
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unsusbstituted isocoumarins, has been reported.11 In some cases the above mentioned strategies
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DOI: 10.1039/C8OB00436F
involving a CH activation step, require high reaction temperatures (120 °C).10b,11
All these approaches are interesting and valuable, but in some cases, they display some limitations,
such as moderate product yields, regioselectivity issues, limited scope, the requirement of harsh
conditions and high temperatures, the need for more-than-stoichiometric amount of promoters or sub-
stoichiometric catalyst loadings, the need of expensive catalytic systems. For these reasons, the
development of alternative approaches based on less explored and cheap catalysts, such as silver salts,
is still an interesting challenge for synthetic organic chemists. In this regards, Wakamatsu12 in 1995,
Bellina13 in 2000, and Shindo14 in 2009 reported the only three examples of silver promoted synthesis
of 3-substituted isocoumarins or pyran-2-ones starting from the corresponding -alkynyl carboxylic
acids. In all these works the scope was not extensively explored, the amount of metal catalyst used
(as Ag(I) salts or Ag powder) was relatively high (10-20 mol%) and some regioselectivity
complications were encountered.
In the last decade, we spent many efforts in the study of new advantageous silver catalysed approaches
for the synthesis of oxygen containing heterocycles starting from alkyne derivatives.15 We were
pleased to report here our results on the AgOTf/p-TSA co-catalysed synthesis of isocoumarins
starting from 2-alkynyl benzoic ester derivatives. To explore the robustness of the approach, it was
also applied to the preparation of two thieno[2,3-c]pyran-7-ones16 starting from methyl 3-
alkynylthiophene-2-carboxylates. The strong advantages of our approach are mild reaction
conditions, selectivity, low catalyst loading, high yields. Finally, the mechanism was in-depth
investigated by 1H NMR studies, isotope-exchange experiments and tests under controlled conditions.
RESULTS and DISCUSSION
The cyclization of methyl 2-(p-tolylethynyl)benzoate 1a was chosen as model reaction to screen
among different silver-based catalytic systems and to find the optimal reaction conditions (Table 1).
We made the firsts attempts in some solvents with different relative polarity17 (i.e., toluene,
dichloroethane, tetrahydrofuran and ethanol) in the presence of 10 mol% of silver triflate at room
temperature (Table 1, entries 1-4). Under these conditions, the starting product 1a was detected by
tlc analysis unmodified after 24 h reaction. Then, 30 mol% of p-TSA· H2O was added in each of the
four reactions and the progress of the reactions was monitored by tlc after 4.5 h. This check revealed
that only the reaction in DCE had started (Table 1, entry 2) whereas in the other solvent the reaction
seemed to be fixed. Therefore, while the former (Table 1, entry 2) was left to react at rt the other three
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(Table 1, entries 1, 3 and 4) were heated at 70 °C. After additional 21 h reaction, wDeOoI: b10s.1e0r3v9/eCd8OtBh0a0t436F
only the reactions performed in DCE and toluene gave the desired isocoumarin 2a in satisfying yields
(Table 1, entries 1 and 2) but the advantage of using DCE was that the reaction proceeded at rt yet.
For this reason, DCE was selected as the solvent of choice. Next, we tested three other silver salts
with counterions with different coordinating properties,18 and we verified that a more coordinating
anion such as nitrate gave worse results (Table 1, entry 5), whereas weaker anions as
hexafluoroantimonate and tetrafluoborate (Table 1, entries 6 and 7) were slightly less effective than
triflate. The concentration of the substrate seemed to have a little effect on the course of the reaction
(Table 1, entries 8 and 9), as expected for an intramolecular transformation, although under dilute
conditions yields are a little lower. Afterwards, we tried to reduce the amount of catalyst and additive
(Table 1, entries 10-13). Although it became necessary a slight rise of temperature to 60 °C to speed
up the reaction, we were pleased to find that the silver catalyst loading could be reduced from 10
mol% to 1 mol% without sensible reduction of yields (Table 1, entries 10 and 11). Conversely, the
reduction of Brønsted acid amount from 30 to 10 mol% resulted in a drop of yields both at rt and at
60 °C (Table 1, entries 12 and 13). A simultaneous reduction of the amount of the silver salt and the
acid to 2 mol% strongly hampered the reaction (Table 1, entry 14). Finally, performing the reaction
directly at 60 °C under these optimized reaction conditions isocoumarin 2a was obtained in 85%
isolated yield in only 2 h (Table 1, entry 15).
As control experiments, we performed five reactions under special conditions (Table 1, entries 16-
20). In the absence of silver triflate, both at rt and at 60 °C (Table 1, entries 16 and 17), the cyclization
product 2a was obtained in lower yields and only after a one day reaction time, thus confirming the
dramatic effect of the silver on the reaction rate and product yield. The reaction was also tried with
the Brønsted acid alone or the silver catalyst alone, in the presence one equivalent of ethanol as proton
shuttle (Table 1, entries 18 and 19), but also under these conditions the reaction gave scarce results
or completely failed, respectively, even after a 24h reaction time. Finally, to exclude a possible direct
involvement of triflic acid eventually generated in situ by reaction of silver triflate and DCE19
a
control experiment was made in the presence of 1 mol% of the superacid, but also in this case the
yields are limited and the reaction is slow. All these evidences seem to confirm the importance of a
fine-tuned cooperative action of the silver catalyst and the p-toluenesulfonic acid.20
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Table 1. Optimization of the reaction conditions.
Catalyst
(mol%)
p-TSA· H2O
2a yielda
(%)
1a rec.
[1a] M
T (°C) / t (h)
Entry
Solvent
(mol%)
yielda (%)
0.250
0.250
0.250
0.250
0.250
0.250
0.250
0.125
0.500
0.250
0.250
0,250
0.250
0.250
0.250
0.250
0.250
0.250
0.250
0.250
AgOTf (10)
AgOTf (10)
AgOTf (10)
AgOTf (10)
AgNO3 (10)
(30)b
(30) b
(30) b
(30) b
(30)
Toluene
DCE
EtOH
THF
90
9
1
rt/4.5  70/21
rt/4.5  rt/21
rt/4.5  70/21
rt/4.5  70/21
rt/21
87 (75)
16
6
2
82
-
3
-
4
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCEc
DCEc
DCE
28
72
13
30
21
9
5
AgSbF6 (10) (30)
rt/21
79
6
AgBF4 (10)
AgOTf (10)
AgOTf (10)
AgOTf (5)
AgOTf (1)
AgOTf (10)
AgOTf (10)
AgOTf (2)
AgOTf (1)
-
(30)
(30)
(30)
(30)
(30)
(10)
(10)
(2)
rt/21
70
7
rt/21
78
8
rt/21
90
9
91
9
10
11
12
13
14
15
16
17
18
19
20
rt/24  60/15
rt/24  60/15
rt/21
94
3
38
58
57
90
8
60/17
35
60/24
9
(30)
(30)
(30)
(30)
-
60/2
90 (85)
31
rt/24
68
43
(65)
(96)
(20)
-
70/24
56
-
60/24
(22)
-
AgOTf (1)
60/24
HOTf (1)
(30)
60/24
(45)
a Yields calculated via 1H NMR using dibromomethane (3 µL, 0,043 mmol) as internal standard. In parenthesis yields of pure isolated
product. b Added after 24 h reaction at rt. c With 1 equiv. of ethanol.
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Next, we tested scope and limitations of the approach under the best reaction conditions achieved
DOI: 10.1039/C8OB00436F
(Table 1, entry 15). We selected some methyl 2-alkynyl-(hetero)arylcarboxylate derivatives
characterized by the presence on the alkyne moieties of alkyl or (hetero)aryl group with different
substituent with electron-donating or electron withdrawing properties (1a-u). Compounds 1a-u were
synthesized by means of a typical Sonogashira coupling21 in good to excellent yields starting from
methyl 2-alkynyl-(hetero)arylcarboxylate and suitable terminal acetylenes (see Supporting
Information). Starting material 1a-u were reacted under optimized conditions and the results are
reported in Scheme 1. In most cases, the reactions gave the desired products in very good yields. The
approach well tolerated the presence of EDGs (2a-e) as well as EWGs (2f-j) in all the positions of
the aryl terminus of the alkyne moiety, except for the bulky nitro group in the ortho position that
resulted in lower yield of isocoumarin 2k. Notably, also an unprotected hydroxy substituent (2e) and
the unusual nitrile group (2g) did not affect with the reaction course. Starting from methyl 2-(3,3-
diethoxyprop-1-yn-1-yl)benzoate 1l, the corresponding 1-oxo-1H-isochromene-3-carbaldehyde 2l
was directly obtain in 44% yields. Such result is remarkable for its potential application as a one-step
total synthesis of artemidinal, a natural isocoumarin isolated from the epigeal part of Artemisia
dracunculus.22 Alkyl alkynes derivatives (2m, n) were obtained in slightly lower yields, while the
reaction of the trimethylsilylacetylene derivative (1o) gave a mixture of unidentified products even
after a prolonged reaction time.23 Thiophene substituted methyl 2-alkynylbenzoate and methyl 3-
(arylethynyl)thiophene-2-carboxylates reacted quickly to give the corresponding 2H-pyran-2-one
cyclization products in excellent yields (2p-r). Conversely, the presence of a pyridine as substituent
on the methyl 2-alkynylbenzoate moiety or as methyl 2-(arylethynyl)nicotinate completely forbid the
reaction (2s,t), and the starting materials were quantitatively recovered unreacted. The pyridine ring
and heteroaromatic analogues are known to strongly coordinate Lewis acids such as silver triflate.
We envisaged that a complete protonation of the pyridine ring could have left the catalyst free to
coordinate the triple bond. However, also rising the amount of p-TSA to 1.3 equiv. the desired
products were not obtained, and the starting materials were quantitatively recovered. On the other
hand, we were pleased to find that also substitutions with ED or EW groups on the benzoic acid ring
are well tolerated, but the reactions require a prolonged reaction time (2u,v).
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Scheme 1. Scope and limitations of the approach (isolated yields).
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A particular behavior has been observed reacting alkyne 1w (Scheme 2). Under the stDaOnId: 1a0r.1d03r9e/Ca8cOtiBo00n436F
condition the only product obtained was the ,-unsaturated ketone 3a, resulting from a Lewis-acid
catalysed Meyer-Schuster rearrangement.24
Scheme 2. Reactivity of 1w.
Finally, to test the scalability of the approach, the model reaction was performed in gram scale (1g of
1a, 4 mmol) obtaining the desired product 2a in 93% isolated yields, in 3 h. Moreover, the scale-up
allowed a further reduction of an half of the catalyst loading (0.5 mol% AgOTf).
Based on our results and previous literature findings, we suggest a plausible reaction mechanism, as
depicted in Scheme 3. The first step involves the coordination of the triple bond by silver that
enhances the electrophilicity of alkyne. The following regiospecific 6-endo-dig intramolecular
nucleophilic attack of the carbonyl oxygen to the electron-deficient alkyne forms the
isochromenylium cation25 (A, A’), stabilized by resonance. The adventitious water removes the
methyl group from intermediate A’ to give the silver -complex B and a molecule of protonated
methanol,26 which is probably responsible for the regeneration of the p-TSA required for the
formation of the final product 2 by protodemetallation.
Scheme 3. Proposed mechanism.
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1
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To gain insight into the mechanism, H NMR studies have been performed. The reaDcOtiIo: 1n0.1o0f391/Ca8OwB0a0s436F
carried out in the presence of AgOTf (1 mol%) and p-TSA· H2O (30 mol%) at 25 °C in deuterated
dichloromethane in a NMR test tube, and a number of spectra were recorded at regular intervals
during 18 hours (Figure 1). Confirming our mechanistic hypothesis, the analysis of the spectra reveals
the appearance of the signal of the methyl group of methanol between 3.46-3.56 ppm. The small
variation of chemical shift observed for this signal during the course of the reaction suggested and
validate the presence of related protonated species in equilibrium under the acidic conditions. As
comparison, the spectra of methanol and protonated methanol were recorder and reported in the
bottom of figure 1. At the same time, the signals of the methoxy ester of 1a at 3.98 ppm decreased
while the C4-H signal of isocoumarin 2a at 7.05 ppm appeared and raised. Also for this latter signal,
the very small deviation of chemical shift during the course of the reaction could be related to the
presence of equilibria between protonated species of 2a (Figure 1).
Figure 1. 1H NMR study.
Afterward, the role of Brønsted acid in the protodemetallation step was verified by reacting the alkyne
1a under standard condition with 30 mol% of deuterated of p-TSA-d · D2O.27 The reaction was
complete in 7 h at 60 °C to give 2a in 86% yields. The analysis of the 1H-NMR spectra of the purified
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product 2a showed a strong reduction (-50%) of the integral of the signal at 6.91DpOpI: m10.,10w39h/Ci8cOhB0i0s436F
associated to the resonance of the proton bonded in position 4 of the isocoumarin nucleus (Figure 2).
Figure 2. Isotope exchange study.
Finally, the key role of adventitious water was confirmed by carrying-out the model reaction under
anhydrous conditions (nitrogen atmosphere, p-TSA previously dried by treatment with 4 Å molecular
sieves and the presence 4 Å molecular sieves in the reaction mixture). The reaction became very slow
and only about 35% of product 2a was obtained after a prolonged reaction time (21 h), beside about
60% of unreacted 1a (yields calculated via 1H NMR using CH2Br2 as internal standard).
CONCLUSIONS
We reported herein a useful synthesis of isocoumarins by a AgOTf/p-TSA co-catalysed cyclization
of 2-alkynyl benzoic ester derivatives. The reaction occurs in a 6-endo-dig regiospecific fashion and
it is characterised by mild reaction condition, broad scope, low metal catalyst loading and in general
very good yields. The versatility of the approach was also briefly explored by the synthesis of two
thieno[2,3-c]pyran-7-ones starting from methyl and methyl 3-alkynylthiophene-2-carboxylates. The
reaction was unsuccessful only in the presence of pyridine derivatives (probably due to a strong
complexation of the metal catalyst) or trimethylsililacetylene group. The synthesis demonstrated to
be easily scalable to gram scale allowing an additional reduction of silver catalyst loading. The
1
mechanism was investigated by H NMR studies, isotope exchange tests, and experiments under
controlled conditions. By this way, the importance of a fine-tuned ratio among Lewis (AgOTf) and
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Brønsted (p-TSA) acids has been pointed out and their peculiar cooperative action has been
DOI: 10.1039/C8OB00436F
established.
CONFLICTS OF INTEREST: There are no conflicts to declare.
ACKNOWLEDGEMENTS: This research was supported by a grant from Università degli Studi di
Milano, Linea 2 “Dotazione Annuale per Attività Istituzionali” 2017. The authors are grateful to
Donatella Nava for NMR experiment, and to Jessica Carbonaro and Fabiola Curti for lab assistance.
ELECTRONIC SUPPLEMENTARY INFORMATION (ESI) AVAILABLE: General
experimental details, procedures, characterization data, and NMR spectra.
REFERENCES
1 R. D. Barry, Chem. Rev., 1964, 64, 229.
2 A. Saeed, Eur. J. Med. Chem., 2016, 116, 290.
3 A. Saeed and F. A. Larik, Chem. Heterocycl. Compd., 2016, 52, 450.
4 Z. Ashraf, Chem. Heterocycl. Compd., 2016, 52, 149.
5 A. Saeed, M. Haroon, F. Muhammad, F. A. Larik, E.-S. Hesham and P. A. Channar, J. Organomet. Chem., 2017, 834,
88.
6 Some recent representative examples: (a) M. Uchiyama, H. Ozawa, K. Takuma, Y. Matsumoto, M. Yonehara, K. Hiroya
and T. Sakamoto, Org. Lett., 2006, 8, 5517; (b) G. Le Bras, A. Hamze, S. Messaoudi, O. Provot, P.-B. Le Calvez, J.-D.
Brion and M. Alami, Synthesis, 2008, 1607; (c) G. Zhao, L.-Z. Yuan, M. Roudier, J.-F. Peyrat, A. Hamze, J.-D. Brion,
O. Provot and M. Alami, Synthesis, 2016, 48, 3382.
7
(a) M. Biagetti, F. Bellina, A. Carpita, P. Stabile and R. Rossi, Tetrahedron, 2002, 58, 5023; (b) T. Yao and R. C.
Larock, J. Org. Chem., 2003, 68, 5936; (c) R. Mancuso, C. C. Pomelli, F. Malafronte, A. Maner, N. Marino, C. Chiappe
and B. Gabriele, Org. Biomol. Chem., 2017, 15, 4831; (d) D. J. Faizi, A. Issaian, A. J. Davis, and S. A. Blum, J. Am.
Chem. Soc., 2016, 138, 2126.
8 Some representative examples: (a) A. Speranca, B. Godoi, S. Pinton, D. F. Back, P. H. Menezes and G. Zeni, J. Org.
Chem., 2011, 76, 6789; (b) A. S. K. Hashmi, C. Lothschuetz, R. Doepp, M. Ackermann, J. De Buck Becker, M. Rudolph,
C. Scholz and F. Rominger, Adv. Synth. Catal., 2012, 354, 133; (c) N. A. Mallampudi, G. S. Reddy, S. Maity and D. K.
Mohapatra, Org. Lett., 2017, 19, 2074; (d) P. Zhao, D. Chen, G. Song, K. Han and X. Li, J. Org. Chem. 2012, 77, 1579;
(e) H. Wang, X. Han and X. Lu, Tetrahedron, 2013, 69, 8626; (f) J. Zhang, X. Han and X. Lu, J. Org. Chem., 2016, 81,
3423; (g) R. Umeda, S. Yoshikawa, K. Yamashita and Y. Nishiyama, Heterocycles, 2015, 91, 2172.
9 Some recent representative examples: (a) V. Subramanian, V. R. Batchu, D. Barange, and M. Pal, J. Org. Chem., 2005,
70, 4778; (b) M. Sun, L. Su, J. Dong, L. Liu, Y. Zhou and S.-F. Yin, Tetrahedron Lett., 2017, 58, 2433; (c) R.G. Chary,
G. R. Reddy, Y. S. S Ganesh K. V. Prasad, S. K. P. Chandra, S. Mukherjeec and M. Pal, RSC Adv., 2013, 3, 9641; (d) M.
R. Kumar, F.M. Irudayanathan, J.H. Moon and S. Lee Adv. Synth. Catal., 2013, 355, 3221.
10
Some recent representative examples: (a) S. Warratz, C. Kornhaaß, A. Cajaraville, B. Niepçtter, D. Stalke and L.
Ackermann, Angew. Chem. Int. Ed., 2015, 54, 5513; (b) L. Ackermann, J. Pospech, K. Graczyk and K. Rauch, Org. Lett.,
2012, 14, 930; (c) D. A. Frasco, C. P. Lilly, P. D. Boyle, and E. A. Ison, ACS Catal., 2013, 3, 2421.
11 G. Jiang, J.X. Li, C. Zhu, W. Wu and H. Jiang, Org. Lett., 2017, 19, 4440.
12 Y. Ogawa, M. Maruno and T. Wakamatsu, Heterocycles, 1995, 41, 2587.
13 F. Bellina, D. Ciucci, P. Vergamini and R. Rossi, Tetrahedron, 2000, 56, 2533.
14 T. Yoshlkawa and M. Shindo, Org. Lett., 2009, 11, 5378.
15
Some representative recent examples: (a) M. Dell’Acqua, G. Abbiati, A. Arcadi and E. Rossi, Org. Biomol. Chem.,
2011, 9, 7836; (b) M. Dell’Acqua, B. Castano, C. Cecchini, T. Pedrazzini, V. Pirovano, E. Rossi, A. Caselli and G.
Abbiati, J. Org. Chem., 2014, 79, 3494; (c) M. Trose, M. Dell’Acqua, T. Pedrazzini, V. Pirovano, E. Gallo, E. Rossi, A.
Caselli and G. Abbiati, J. Org. Chem., 2014, 79, 7311; (d) G. Tseberlidis, M. Dell'Acqua, D. Valcarenghi, E. Gallo, E.
Rossi, G. Abbiati and A. Caselli, RSC Adv., 2016, 6, 97404; (e) M. Dell'Acqua, V. Pirovano, S. Peroni, G. Tseberlidis,
D. Nava, E. Rossi and G. Abbiati, Eur. J. Org. Chem., 2017, 1425.
16 M. S. Rao, M. Haritha, N. Chandrasekhar, M. V. Basaveswara Rao and M. Pal, Tetrahedron Lett., 2014, 55, 1660.
17 C. Reichardt, Solvents and Solvent Effects in Organic Chemistry, 3rd ed., Wiley-VCH, Weinheim, 2003.
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DOI: 10.1039/C8OB00436F
18 R. Díaz-Torres and S. Alvarez, Dalton Trans., 2011, 40, 10742.
19 T. T. Dang, F. Boeck and L. Hintermann, J. Org. Chem., 2011, 76, 9353.
20 M. Hellal, J.-J. Bourguignon and F. J.-J. Bihel, Tetrahedron Lett., 2008, 49, 62.
21 (a) K. Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron Lett., 1975, 50, 4467. For some recent reviews see: (b) R.
Chinchilla and C. Nájera, Chem. Rev., 2007, 107, 874; (c) R. Chinchilla and C. Nájera, Chem. Soc. Rev., 2011, 40, 5084.
22 A. Mallabaev, I. M. Saitbaeva and G. P. Sidyakin, Chem. Nat. Compd. 1971, 7, 248.
23 Troubles in similar silver catalyzed cyclization of trimethylsilylacetylene derivatives were already observed (ref. 15b,e).
24 (a) Y. Zhu, L. Sun, P. Lu and Y. Wang, ACS Catalysis, 2014, 4, 1911; (b) D. A. Engel and G. B. Dudley, Org. Biomol.
Chem., 2009, 7, 4149.
25 (a) Belmont, P. in Silver in Organic Chemistry, Ed. M. Harmata, John Wiley and Sons, Hoboken, 2010, Chapter 5, pp
143–165; (b) G. Fanga and X. Bi, Chem. Soc. Rev., 2015, 44, 8124.
26 A similar removal of methyl group by ethanol was recently proposed (ref. 6c).
27 For the procedure of deuteration of p-TSA see ESI.
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DOI: 10.1039/C8OB00436F
Silver Triflate/p-TSA Co-Catalysed Synthesis of 3-Substituted
Isocoumarins from 2-Alkynylbenzoates
Jonathan Gianni, Valentina Pirovano, Giorgio Abbiati*
GRAPHICAL ABSTRACT
GRAPHICAL ABSTRACT SHORT TEXT: A
well-balanced composition of the catalytic system
partners make the approach cheap, quick,
regioselective, mild, general, scalable and high-
yielding.