Acid catalysed rearrangement of isobenzofurans to angularly fused phthalides

Article abstract of DOI:10.1039/c9ob00708c

An acid catalysed, cascade process for the construction of angularly fused polycyclic phthalides from isobenzofurans under transition metal free conditions has been reported. This process is very general for diverse gem-disubstituted isobenzofuran substrates. Control experiments supported the mechanism as the nucleophilic attack of the carboxylate onto the acid activated furan ring for the simultaneous ring closing-ring opening cascade followed by dehydration. This method serves as a greener alternative for the synthesis of angularly fused polycyclic phthalides.

Full text of DOI:10.1039/c9ob00708c

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: B. Baire, B. S.
Chinta and S. Gandhi, Org. Biomol. Chem., 2019, DOI: 10.1039/C9OB00708C.
This is an Accepted Manuscript, which has been through the
Volume 14 Number
1 7 January 2016 Pages 1–372
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
rsc.li/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 6
View Article Online
DOI: 10.1039/C9OB00708C
Method
Acid Catalysed Rearrangement of Isobenzofurans to Angularly
Fused Phthalides
Received 00th January 20xx,
Accepted 00th January 20xx
Bhavani Shankar Chinta,[a] Soniya Gandhi[a] and Beeraiah Baire*[a]
DOI: 10.1039/x0xx00000x
www.rsc.org/
An acid catalysed, cascade process for the construction of angularly fused polycyclic phthalides from isobenzofurans under
transition metal free conditions has been reported. This process is very general for diverse gem-disubstituted
isobenzofuran substrates. Control experiments supported the mechanism as the nucleophilic attack of the carboxylate on
to the acid activated furan ring for the simultaneous ring closing-ring opening cascade followed by dehydration. This
method serves as a greener alternative for the synthesis of angularly fused polycyclic phthalides.
intramolecular or intermolecular fashion (Figure 1).7 In this method
the angular phthalide has been generated from an acyclic precursor.
Few other methods involving the generation of the lactone ring as
Introduction
Phthalides (isobenzofuranones) and their derivatives are ubiquitous
in bioactive natural products and drugs (Figure 1).1 They are found
to exhibit antibacterial, antiviral and anti-hypertensive activities.2
They are also employed as versatile building blocks in organic
synthesis,3 for the generation of complex polycyclic systems, e.g.,
key precursors in the Hauser annulation process.4 Owing to their
importance several synthetic methods have already been
developed in literature for the efficient generation of bicyclic as
well as polycyclic phthalides. Most of the processes for the
synthesis bicyclic phthalides employ the ortho-functionalized,
aromatic carbonyl derivatives as starting materials.5
the key step have also been reported.8 Herein, we designed and
developed an acid catalysed, cascade rearrangement process for an
efficient generation of angularly fused polycyclic phthalides, from
corresponding isobenzofurans. We have also developed a one pot
thermal [4+2] cycloaddition followed by acid promoted
rearrangement process from acyclic enyne-alkyne precursors.
According to our design (Scheme 1), in presence of an acid
(Lewis as well as Brønsted), a linearly fused iso-benzofuran I
possessing a carboxylate group on the 3rd-position of the arene,
may involve a rearrangement cascade to generate the angularly
fused phthalide II. This transformation either may involve a
sequential ring opening-ring closing process via the hydroxy-ester III
(path a) or simultaneous ring closing-ring opening process (path b)
via hydroxy-lactone IV. Nevertheless, both the pathways represent
a self-relay acid catalysis mechansim.9
Figure 1 Angularly fused polycyclic phthalide natural products and most commonly
used transition metal-catalysed [2+2+2] cycloaddition approach to these frameworks.
Polycyclic phthalides can have either
a linear or angular
Scheme 1 Our design for an acid catalysed rearrangement approach to angularly fused
phthalides.
arrangement of the fused rings with respect to the
isobenzofuranone moiety. Synthesis of linearly fused polycyclic
phthalides and their derivatives is also well documented in
literature.6 In contrast, the synthetic approaches to polycyclic,
angularly fused phthalides are very scarce. The commonly
employed method is a transition metal [Ni(0), Rh(I), and Ru(I)]
catalysed, [2+2+2] cyclotrimerization of alkynes either in an
Results and discussion
We began our investigation with
a
linearly fused
isonaphthofuran10 1a as the model substrate. When 1a was
treated with 1.2 equiv. of p-TSA at RT in CH2Cl2, no reaction
observed and starting material was recovered after 24 h (Table
1, entry 1). To our delight, increasing the temperature to 55 °C
resulted in the formation of the expected angularly fused
isonaphthofuranone 2a in 97% yield after 2.5 h (entry 2).
Encouraged by this outcome, we next performed an
optimization study to find out the catalytic reaction conditions.
a.Department of Chemistry, Indian Institute of Technology Madras, Chennai-
600036, India.
Email: beeru@iitm.ac.in; Fax: 044-22574202; Tel: 044-22574206;
Electronic Supplementary Information (ESI) available: General procedures for the
preparation of the compounds and the catalytic reaction; Characterization data
including 1H, 13C NMR spectra, IR and HRMS. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 6
Method
Organic Chemistry Frontiers
major isomer. It supports the major compound as E-olefin and
View Article Online
DOI: 10.1039/C9OB00708C
minor as the Z-isomer.
Table 1 Discovery and optimization study. a all the reactions were carried out
on 0.1 mmol of 1a
b yields after chromatographic purification; c solvent is 1,2-
DCE; NR: no reaction
;
MeSO3H (1.2 equiv.) at 55 °C, provided the product 2a in
87% yield (entry 3). With a stronger acid i.e., TfOH (1.2 equiv.,
entry 4) the reaction was faster (1.5 h) and high yielding for 2a
(98%) even at 0 °C to RT. Next, we employed various Lewis
acids. In case of FeCl3 (1.2 equiv.) the reaction was faster (1 h)
and afforded 98% yield of the 2a at 55 °C (entry 5). Other
Lewis acids (entries 6-8) BiCl3 (1.5 equiv., 28 h, 92%), AlCl3 (3
equiv., 28 h, 96%) and BF3.OEt2 (2.4 equiv., 33 h, 96%) also
promoted the reaction very smoothly and efficiently but took
longer reaction times even with higher amounts of acids. We
next performed this reaction with lower amounts of TfOH to
find out the possibility for a catalytic transformation (entries 9-
13). The reaction was slower and less efficient (29 h; 58%) with
0.1 equiv. at RT. As the temperature increases from 55 to
100 °C, the reaction rate and efficiency (62 to 85%) also
increased. Next performing the reaction with 0.2 equiv. of
TfOH resulted in 93% of 2a within 20 min at 100 °C (entry 13)
and we chose this as an optimized condition for the designed
cascade rearrangement.
Scheme 2 Substrate scope study
Next, we performed a scope study for substrates for the
generation of structurally diverse, angularly fused polycyclic
phthalides. Initially, various substituents such as methyl-
methyl, ethyl-phenyl, isopropyl-phenyl, benzyl-phenyl,
cycloalkyl-phenyl, attached at the α-carbon position of linearly
fused isobenzofuran (Scheme 2) were employed. All these
substrates 1b-j smoothly underwent the cascade
rearrangement under standard reaction conditions to afford
the corresponding angularly fused phthalides 2b-j in excellent
yields (68-97%). The geometry of the exo-olefin present in
product 2j was assigned by NOESY (see supporting information
for details). Interestingly, in case of Et-Ph and Bn-Ph substrates
Scheme 3 Substrate scope study of spiroisonaphthofurans
Subsequently,
we
also
employed
spiro-fused
isobenzofurans 3a-g under standard reaction conditions
(Scheme 3). There was no ring size effect observed, when
employed isobenzofurans 3a-e containing various spiro-
cycloalkanes (cyclopentane to cyclooctane). All these
substrates yielded the corresponding angularly fused
phthalides 4a-e in excellent yields (70-95%). In addition,
tetraline and chromane spiro-fused iso-bezofurans 3f and 3g
were also efficiently converted to the corresponding products
1k
& 1l, a (1:0.6) and (1:1) mixture of E:Z-isomers 2k and 2l
were obtained respectively.11 We also employed an
isobenzofuran 1m carrying an unsymmetric quaternary centre
(ethyl,methyl). Here, we have exclusively isolated the products
(E/Z-isomers; 3:1) 2m obtained via the elimination occuring
through ethyl group instead from methyl group. The
configuration across the olefin was confirmed by the NOE
correlations obseved for two methyl groups present in the
4f and 4g
.
At this juncture, we envisioned an opportunity to extend
this strategy for the synthesis of highly functionalized angularly
fused phthalides by incorporating a cyclopropane ring at the
carbon of the isobenzofuran framework. According to our
design (Figure 2), the cyclopropane ring of can be opened-up
-
5
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 6
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
during the rearrangement process and the corresponding
carbocation can be further trapped by various nucleophiles in
View Article Online
DOI: 10.1039/C9OB00708C
a 1,3-fashion to give functionalized benzophthalides 6. Initially,
we focused our attention to perform the reaction by
employing external nucleophiles to open the cyclopropane ring
in the presence of CF3SO3H (the counterion –OTf is non-
nucleophilic) (Figure 2).
Scheme 4 Scope study for cyclopropyl-isobenzofurans and ORTEP diagram
for compound 6f
We also used iodine (I2, 1.2 equiv.) as an electrophilic
promoter and the in situ generated iodide (I-) as the
nucleophile to generate the alkyl iodide 6h in excellent yield
(94%). In all the above cases, the E-isomer was isolated as the
exclusive product and no traces of the corresponding Z-
isomers were obtained. Surprisingly, when we employed the
phenyl-cyclopropyl substrate 5b with all four acids, an
inseparable mixture of E:Z isomers of corresponding
benzophthalide products 7a-d were obtained in good yields. A
single crystal X-ray diffraction analysis for compound 6f
,
unambiguously confirmed the presence of angularly fused
benzophthalide framework.13
After describing a good substrate scope, we performed few
control experiments (Scheme 5) to get insights into the
mechanism and to differentiate between two proposed
pathways (path a & b, Scheme 1). Accordingly, treatment of a
linear isobenzofruan 8a (which lacks ester group)10 under
standard conditions resulted in decomposition of starting
material after 36 h, instead of giving compound 9a via ring
opening reaction. Similarly, the isobenzofuran 8b possessing a
cyclopropyl and lacks the ester group also resulted in
decomposition, upon subjection to standard reaction
conditions.
These observations suggested that, the ester group is
necessary for a smooth ring (furan) opening process. Hence,
this rules out the pathway a, and supports pathway b (Scheme
1) as the possible mechanism i.e., the ester might involve in
the nucleophilic attack on to the acid activated furan ring for
the simultaneous ring closing-ring opening cascade followed
by the acid promoted dehydration. Since, the TfOH is acting as
the catalyst for both the transformations, the overall process
resemebles the self-relay catalysis.9 In pathway b, after the
initial ring opening-ring closing cascade of 10, the dehydration
of resultant tertiary alcohol 11 is dependent on the nature of
the group present at carbinol carbon. When R1 = alkyl; an
exclusive formation of more stable E-olefin 12E (see Scheme 5)
is observed. On the other hand, in case of R1 = aryl; a mixture
of both E- and Z-olefins 13E and 13Z (as evidenced in Scheme 2
and 4) are observed.
Figure 2 Design, optimization and scope study for functionalised angularly
fused phthalides via cyclopropane ring-opening with phenols and methanol
The compound 5a upon subjection to standard reaction
conditions in presence of phenol (2 equiv.), offered the phenol
trapped product 6a (13%) along with hydroxyl trapped product
6a' (11%). After screening various temperatures, equiv., of acid
and phenol (entries 2-7), we found that, phenol (5 equiv.),
TfOH (50 mol%) and RT in CH2Cl2 (entry 7, Table 2) as the best
condition to obtain the phenol trapped product 6a in good
yield. We also employed three different nucleophiles such as
o-cresol, p-cresol and methanol. All these reagents gave the
corresponding products 6b-d (55%, 41% and 87% respectively)
along with 18%, 37% and 0% of 6a' respectively.
Next, the dual (simultaneous catalytic as well as
nucleophilic) behaviour of several acids,12 where their
counterions are good nucleophiles to trap the carbocation,
have also been tested (Scheme 4). Accordingly, when we
treated the substrate 5a (methyl-cyclopropyl) with acids such
as p-TSA (1.2 equiv.), MsOH (1.2 equiv.), and BiCl3 (1.5 equiv.)
in CH2Cl2 at 55 °C; the corresponding counter ions (tosylate,
mesylate and chloride respectively) have efficiently trapped
the carbocation to provide access to angularly fused
benzophthalides 6e-g in excellent yields. Interestingly, when
the reaction was employed with FeCl3 (1.2 equiv.), the
hydroxyl trapped compound 6a' was obtained as the sole
product in 75% yield.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 6
Method
Organic Chemistry Frontiers
View Article Online
DOI: 10.1039/C9OB00708C
Table 2 One pot TDDA-skeletal rearrangement process
Scheme 5 a) Control experiments; b) possible mechanism
Conclusions
We have also extended this methodology for the synthesis
of simple phthalides. Accordingly, isobenzofurans 14a and 14b
were subjected to standard reaction conditions (Scheme 6).
Both substrates underwent smooth rearrangement to yield the
corresponding phthalides 15a and 15b in excellent yields (85%
and 78% respectively) after 2 h. These two phthalide
structures 15a and 15b represent the tricyclic frameworks
present in bioactive natural products alcyopterosin M and
cryptoacetalide respectively (see Figure 1).
In conclusion, we have designed and developed an acid
catalyzed, cascade process for the construction of angularly
fused polycyclic phthalides from isobenzofurans. This process
found to exhibit a very broad scope for various gem-
disubstituted isobenzofuran substrates. Including the
cyclopropane as one of the substituent and trapping the
carbocation by various external nucleophiles provided
structurally diverse angularly fused phthalide frameworks.
Control experiments supported the mechanism as the
nucleophilic attack of the carboxylate on to the acid activated
furan ring for the simultaneous ring closing-ring opening
cascade followed by dehydration. This metal free approach for
the angularly fused polycyclic phthalides can serve as a
greener alternative.
Scheme 6 Synthesis of frameworks of bioactive natural products
Finally, to improve the synthetic efficiency of this cascade
rearrangement, we also designed and developed a one pot
strategy for the synthesis of angular phthalides directly from
the corresponding enyne-alkyne precursors, without the
isolation of isobenzofuran product after the tetradehydro
Diels-Alder (TDDA) reaction (Table 2).14 The substrate 1a' upon
heating at 100 °C in 1,2-DCB and phenol (10 equiv.), smoothly
underwent the [4+2]cycloaddition reaction. After completion
of 1a' (25 h), TfOH (20 mol%) was added to the reaction
mixture and then continued the heating for 30 min at same
temperature (entry 1, Table 1) to give the phthalide 2a in 51%
overall yield. Increase in the reaction temperature to 150 °C
resulted in decreased yield (44%) of 2a (entry 2). Next, we
performed the TDDA reaction of 1a' at 150 °C followed by the
rearrangement reaction of the resultant 1a at 100 °C (entry 3).
This combination gave an improved yield of 2a (58%).
Subsequently, two more substrates 3a' and 1b' were subjected
to this one pot strategy, employing the conditions of entry 3
(Table 2). The overall yields obtained were good for the
corresponding angular phthalides 4a (59%) and 2b (57%). A
cyclopropyl containing substrate 5e' has also been efficiently
employed in this one pot strategy using pTSA to generate the
phthalide 6e (53%). This one pot methodology represents an
exact alternative strategy to the metal catalysed [2+2+2]
cycloaddition approaches for the angular phthalides (see
Figure 1).
Acknowledgements
We thank Indian Institute of Technology Madras, Chennai for
the infrastructural facilities. We thank SERB-INDIA for funding
through EMR/2016/000041 grant. BSC thanks IIT Madras for
HTRA fellowship. We thank Mr Ramkumar for single crystal X-
ray analysis.
Notes and References
1
(a) J. J. Beck and S.-C. Chou, J. Nat. Prod. 2007, 70, 891; (b) G.
J. Calton, C. S. Cobbs and J. P. Hamman, In Manual of
Industrial Microbiology and Biotechnology; A. S. Demain and
N. A. Solomon, Eds.; American Society for Microbiology: WA,
1986, 436.
(a) G. Lin, S. S.-K. Chan, H.-S. Chung and S.-L. Li, Chemistry
and Biological Action of Natural Occurring Phthalides. In
Studies in Natural Products Chemistry; A. Rahman, Ed.;
Elsevier: Amsterdam, 2005, 32, 611; (b) J. J. Beck and S. C.
Chou, J. Nat. Prod. 2007, 70, 891; (c) M.-J. Xioang and Z.-H.
Li, Curr. Org. Chem. 2007, 11, 833; (d) A. D. Mola, L. Palombi
and A. Massa, Curr. Org. Chem. 2012, 16, 2302.
(a) V. Snieckus, Chem. Rev. 1990, 90, 879; (b) D. Mal and P.
Pahari, Chem. Rev. 2007, 107, 1892; (c) C. D. Donner,
Tetrahedron 2013, 69, 3747; ( ,
and C. P. Vlaar, Tetrahedron Lett. 2007, 48, 8972; (e) K.
Rathwell and M. A. Brimble, Synthesis 2007, 643; (f) A. S.
Mitchell and R. A. Russell, Tetrahedron 1995, 51, 5207.
2
3
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 6
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
4
(a) M. Watanabe, H. Morimoto, K. Nogami, S. Ijichi and S.
J. Org. Chem. 2017, 3381; (e) H. Takikawa, T. HVaieswhiAmrtioclteoO,nMline.
Matsuura, T. Tashiro, T. Kitahara, KD. OMI:o10ri.10a3n9d/CM9O.B0S0a7s0a8kCi,
Tetrahedron Lett., 2008, 49, 2258; (f) S. Neufeind, N. Hlsken,
J.-M. Neudçrfl, N. Schlçrer and H.-G. Schmalz, Chem. Eur. J.
2011, 17, 2633.
Furukawa, Chem. Pharm. Bull. 1993, 41, 968; (b) C. Cox and
S. J. Danishefsky, Org. Lett. 2000, 2, 3493; (c) N. J. P. Broom
and P. G. J. Sammes, Chem. Soc. Chem. Commun. 1978, 162;
(d) M. A. Brimble, S. I. Houghton and P. D. Woodgate,
Tetrahedron 2007, 63, 880; (e) P. Asenjo, F. Farina, M.V.
9
(a) N. T. Patil, V. Singh, A. Konala and A. K. Mutyala,
Tetrahedron Lett., 2010, 51, 1493; (b) N. T. Patil, R. D.
Martin, M. C. Paredes and J. J. Soto, Tetrahedron 1997, 53
1823; (f) H. W. Moore and R. Czerniak, Med. Res. Rev. 1981,
, 249.
,
Kavthe, V. S. Shinde and B. Sridhar, J. Org. Chem., 2010, 75
,
1
3371; (c) N. T. Patil, A. K. Mutyala, P. G. V. V. Lakshmi, B.
Gajula, B. Sridhar, G. R. Pottireddygari and T. P. Rao, J. Org.
Chem., 2010, 75, 5963; (d) N. T. Patil and V. Singh, Chem.
Commun., 2011, 47, 11116; (e) N. T. Patil, V. S. Shinde and B.
Gajula, Org. Biomol. Chem., 2012, 10, 211.
5
(a) G. Yang and W. Zhang, Org. Lett. 2012, 14, 268; (b) D. Mal
and S. Dey, Tetrahedron 2006, 62, 9589; (c) A. I. Meyers and
W. B. Avila, J. Org. Chem. 1981, 46, 3881; (d) J. N. Freskos, G.
W. Morrow and J. S. Swenton, J. Org. Chem. 1985, 50, 805.
6
7
(a) D. Mal and P. Pahari, Chem Rev. 2007, 107, 1892; (b) R. 10 B. S. Chinta and B. Baire, Eur. J. Org. Chem. 2017, 23, 3381.
Karmakar, P. Pahari and D. Mal, Chem. Rev. 2014, 114, 6213. 11 The diastereomeric E/Z ratios for various compounds were
(a) X. Bugaut, X. Guinchard and E. Roulland, J. Org. Chem.
2010, 75, 8190; (b) K. Tanaka, T. Osaka, K. Noguchi and M. 12 P. Tharra, B. Baire, Chem. Eur. J. 2017, 23, 2014.
Hirano, Org. Lett. 2007, , 1307; (c) K. Tanaka, Y. Sawada, Y. 13 X-ray diffraction analysis data for 6f has been deposited with
measured by 1H NMR spectroscopy.
9
Aida, M. Thammathevo, R. Tanaka, H. Sagae and Y. Otake,
Tetrahedron 2010, 66, 1563; (d) T. Kawasaki, S. Saito and Y.
Yamamoto, J. Org. Chem. 2002, 67, 2653; (e) R. Grigg, R.
the Cambridge Crystallographic Data Centre with
CCDC1846904. Further details are given in the Supporting
Information (Table 1).
Scott and P. Stevenson, Tetrahedron Lett. 1982, 23, 2691; (f) 14 (a) A. Michael and J. E. Bucher, Chem. Zentrblt., 1898, 731;
R. Grigg, R. Scott and P. Stevenson, J. Chem. Soc. Perkin (b) O. Diels and K. Alder, Justus Liebigs Ann. Chem. 1928,
Trans. 1988, , 1357; (g) S. Levin, R. R. Nani and S. E. 460, 98; (c) P. Wessig and G. Müller, Chem. Rev. 2008, 108
Reisman, J. Am. Chem. Soc. 2011, 133, 774; (h) P. Bhatarah,
E. H. Smith, J. Chem. Soc. Perkin Trans. 1992, , 2163; (i) B.
1
,
2051; (d) R. L. Danheiser, A. E. Gould, R. F. Pradilla and A. L.
Helgason, J. Org. Chem. 1994, 59, 5514; (e) J. R. Dunetz and
R. L. Danheiser, J. Am. Chem. Soc. 2005, 127, 5776; (f) M. E.
1
Witulski, A. Zimmermann and N. D. Gowans, Chem.
Commun. 2002, 2984; (j) Y. Zou and A. Deiters, J. Org. Chem.
2010, 75, 5355.
(a) D. F. Chorley, J. L.-Y. Chen, D. P. Furkert, J. Sperry and M.
A. Brimble, Synlett 2012, 23, 1280; (b) C.-W. Chang and R.-J.
Chein, J. Org. Chem. 2011, 76, 4154; (c) L. C. Henderson, W.
A. Loughlin, I. D. Jenkins, P. C. Healy and M. R. Campitelli, J.
Org. Chem. 2006, 71, 2384; (d) B. S. Chinta and B. Baire, Eur.
Hayes, H. Shinokubo and R. L. Danheiser, Org. Lett., 2005, 7,
3917; (g) M. S. B. Wills and R. L. Danheiser, J. Am. Chem. Soc.
1998, 120, 9378; (h) B. S. Chinta, A. Siraswar and B. Baire,
Tetrahedron, 2017, 73, 4178; (i) B. S. Chinta and B. Baire, Eur.
J. Org. Chem., 2017, 3381; (j) B. S. Chinta and B. Baire, Org.
Biomol. Chem., 2017, 15, 5908; (k) B. S. Chinta and B. Baire,
Org. Biomol. Chem., 2018, 16, 262.
8
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 6 of 6
View Article Online
DOI: 10.1039/C9OB00708C
Method
Table of Content Entry Only
Acid Catalysed Rearrangement of Isobenzofurans to Angularly Fused Phthalides
Bhavani Shankar Chinta,[a] Soniya Gandhi[a] and Beeraiah Baire*[a]
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600 036, India
E-mail: beeru@iitm.ac.in; Fax: 044-22574202; Tel: 044-22574206
R1
R1
R1
H
OH R2
R2
H+
TfOH (0.2 eq.)
(simultaneous
ring-opening
ring-closing
cascade)
R2
O
TfOH (0.2 eq.)
(dehydration)
O
O
O
EtO
O
O
angularly fused
TDDA
R1
polycyclic phthalides
One pot strategy
i) 1,2-DCB, 150 °C (TDDA)
ii) TfOH (0.2 eq.) (rearrangement)
R2
O
EtO2C
An acid catalysed, cascade process for the construction of angularly fused polycyclic phthalides from
isobenzofurans via a simultaneous ring closing-ring opening cascade has been reported. This approach serves as a
greener alternative for the angularly fused polycyclic phthalides.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins