Rapid access to 3-indolyl-1-trifluoromethyl-isobenzofurans by hybrid use of Lewis/Br?nsted acid catalysts

Article abstract of DOI:10.1039/d0ob01582b

We report herein a rapid access to 3-indolyl-1-trifluoromethyl-isobenzofurans via a [1,4]-hydride shift/cyclizatin/intermolecular nucleophilic addition reaction sequence. In this process, a Lewis acid promoted internal redox reaction ([1,4]-hydride shift/cyclization) followed by a Br?nsted acid promoted intermolecular reaction (generation of cyclic oxonium cation/intermolecular Friedel-Crafts reaction) occurred to give various 3-indolyl-1-trifluoromethyl-isobenzofurans in good chemical yields.

Full text of DOI:10.1039/d0ob01582b

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: D. Hoshino and K.
Mori, Org. Biomol. Chem., 2020, DOI: 10.1039/D0OB01582B.
Volume 15
Number 47
21 December 2017
Pages 9945-10124
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
Accepted Manuscripts are published online shortly after acceptance,
rsc.li/obc
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
Information for Authors.
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 still apply. In no event
ISSN 1477-0520
PAPER
I . J. Dmochowski et al.
Oligonucleotide modifi cations enhance probe stability for
shall the Royal Society of Chemistry be held responsible for any errors
single cell transcriptome in vivo analysis (TIVA)
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
rsc.li/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 5
View Article Online
DOI: 10.1039/D0OB01582B
Journal Name
COMMUNICATION
Rapid access to 3-indolyl-1-trifluoromethyl-isobenzofurans by
hybrid use of Lewis/Brønsted acid catalysts
Daiki Hoshinoa and Keiji Mori*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
We report herein a rapid access to 3-indolyl-1-trifluoromethyl- of two types of catalysts (Lewis acid and Brønsted acid, lower
isobenzofurans via a [1,4]-hydride shift/cyclizatin/intermolecular part of Scheme 1).
nucleophilic addition reaction sequence. In this process, a Lewis
acid promoted internal redox reaction ([1,4]-hydride
shift/cyclization) followed by
a Brønsted acid promoted
intermolecular reaction (generation of cyclic oxonium
cation/intermolecular Friedel-Crafts reaction) occurred to give
various 3-indolyl-1-trifluoromethyl-isobenzofurans in good
chemical yields.
Recently, our group has been interested in the development
of novel transformations via the intramolecular hydride
shift/cyclization process, namely, the internal redox process.1–5
The important feature of this methodology is that various
useful skeletons could be constructed from simple substrates
in a single operation. Quite recently, we disclosed that the
combination of an internal redox process and an
Scheme 1. [1,4]-Hydride shift/cyclization/intermolecular nucleophilic
addition reaction sequence.
We started our study from the reaction of trifluoromethyl
ketone A having a N,N-dialkylaminomethyl group or an
alkoxymethyl group at ortho position for three reasons
(Scheme 2): (1) potent hydride shift ability due to two factors
(electronic assistance from the adjacent heteroatom (X) and
high electrophilicity of trifluoromethyl ketone);2k,n (2) easy
generation of cation species C/C’, which is important to
achieve the subsequent reaction, through electronic assistance
from the oxygen atom in internal redox adduct B;2n and (3)
absence of hydrogens adjacent to the carbocation in C’
(suppressing the generation of less reactive styrene moiety E).
Among them, the third reason is key to achieving our goal
based on our previous results: isochromene 3 was the only
detectable product when trifluoromethyl ketone 1 having a
phenethyl ether moiety at the ortho position was treated with
5 mol% of Sc(OTf)3 and 1.0 equiv. of various nucleophiles, such
as indole, allyltrimethylsilane, and so on.7
intramolecular Friedel-Crafts reaction is
a
possible
transformation. This sequential system allowed us to access
trifluoromethyl group substituted spiro-isochromans, which
are otherwise difficult to synthesize by conventional methods,
in a highly stereoselective fashion (upper part of Scheme 1).2n,6
A sequential system involving an intermolecular nucleophilic
addition reaction would be a useful synthetic tool for the
concise construction of complex molecules from two
perspectives: (1) no need of the preparation of complex
starting materials, and (2) easy modification of coupling
partner (nucleophile). We report herein the first realization of
a
desired system for the synthesis of 3-indolyl-1-
trifluoromethyl-isobenzofurans based on the hybrid utilization
Department of Applied Chemistry, Graduate School of Engineering, Tokyo
University of Agriculture and Technology. 2-24-16 Nakacho, Koganei, Tokyo 184-
8588, Japan. E-mail: k_mori@cc.tuat.ac.jp. Fax: +81 42-388-7034. Tel: +81 42-
388-7034 ꢀ
† Footnotes related to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. 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 5
COMMUNICATION
Journal Name
led to the recovery of 5a (>52%, entries 2 andVi3ew).ArtiFcluerOtnhliener
DOI: 10.1039/D0OB01582B
screening for catalyst suggested that Brønsted acids were
effective to promote the desired reaction. In the case of
TsOH•H2O, intermolecular adduct 10a was obtained in 33%
chemical yield with 2.1:1 diastereoselectivity, accompanied by
the recovery of 5a (27%, entry 4). Desired adduct 10a was also
generated with TfOH as the acid catalyst, although both
chemical yield and diastereoselectivity were low (20% and d.r.
= 2.0:1, entry 5). Weak Brønsted acid AcOH was ineffective
(5a: 75%, entry 6). Tf2NH was the catalyst of choice, and good
chemical yield was achieved (53%, entry 7). Decreasing the
catalyst loading from 100 mol% to 30 mol% significantly
lowered the chemical yield to 35% (entry 8), clearly indicating
that employment of a stoichiometric amount of Tf2NH was
essential to achieve a good chemical yield.
Scheme 2. Three reasons for selection of starting material and previous
results.
Further screening suggested that the choice of the reaction
solvent had a significant effect on the chemical yield. Although
CH3CN, benzene, and toluene furnished almost identical
results to ClCH2CH2Cl (37–58%, entries 9–11), xylenes and
some electron-deficient aromatic solvents, such as
chlorobenzene and benzotrifluoride, led to the improvement
of the chemical yield (entries 12–16). Among them, o-xylene
and m-xylene were particularly effective, and excellent
chemical yields were realized in both cases (97% and 96%,
respectively, entries 14 and 15)
The first hurdle in the development of the target reaction was
how to achieve the less studied [1,4]-hydride shift8 to
trifluoromethyl ketone. Fortunately, the key [1,4]-hydride
shift proceeded smoothly to afford isobenzofuran 5a in
excellent chemical yield (90%) with low diastereoselectivity
(d.r. = 1.6:1) when a solution of trifluoromethyl ketone 4a
having an N,N-dibenzylaminomethyl group at ortho position in
ClCH2CH2Cl (b.p. 84 °C) was treated with 10 mol% of Yb(OTf)3
at refluxing temperature for 24 h (Scheme 3). Extensive
screening for the substrate revealed that the employment of
4a was essential to achieve the reaction.9,10 For example, both
substrate 6 with a N-benzyl-N-phenyl group and substrate 8
with an ortho-benzyloxymethyl group did not afford
isobenzofurans 7 and 9 even when Yb(OTf)3, which exhibited
the best catalytic performance in the case of 4a, was employed.
Table 1. Examination of reaction conditions.a
Yield [%]b
d.r. c
–
–
–
Entry
Promoter Solvent
10a
0
0
5a
85
77
1d
2
3
Yb(OTf)3
TiCl4
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
BF3•OEt2
0
52
27
45
75
18
44
34
17
50
25
20
trace
trace
trace
Scheme 3 Trial for [1,4]-hydride shift in trifluoromethyl ketone.
4
5
6
7
8e
9
10
11
12
13
14
15
TsOH•H2O ClCH2CH2Cl 33
2.1:1
2.0:1
–
TfOH
ClCH2CH2Cl 20
ClCH2CH2Cl
Stimulated by the excellent result of the [1,4]-hydride
shift/cyclization process, we shifted our interest toward the
subsequent intermolecular nucleophilic addition reaction
(Table 1). To achieve the reaction, we focused on the use of
indole moieties as the nucleophile. We were greatly surprised
that effective methods for the synthesis of 3-indolyl-1-
trifluoromethyl-isobenzofurans are scarce in spite of the
potent biological activity derived from the hybrid structure of
the indole motif and the 1-trifluoromethyl-isobenzofuran
skeleton.11 When a mixture of obtained isobenzofuran 5a and
indole 11a in ClCH2CH2Cl was heated to reflux in the presence
of 10 mol% of Yb(OTf)3, the expected intermolecular reaction
did not proceed, and 5a was recovered almost quantitatively
(85%, entry 1). The use of a stoichiometric amount (100 mol%)
of common strong Lewis acids, such as TiCl4 and BF3•OEt2, also
AcOH
Tf2NH
Tf2NH
Tf2NH
Tf2NH
Tf2NH
Tf2NH
Tf2NH
Tf2NH
Tf2NH
Tf2NH
0
ClCH2CH2Cl 53
ClCH2CH2Cl 35
2.0:1
1.8:1
2.2:1
2.1:1
2.1:1
2.0:1
2.4:1
2.0:1
2.1:1
2.0:1
CH3CN
58
54
37
76
75
97
96
81
benzene
toluene
PhCl
PhCF3
o-xylene
m-xylene
p-xylene
16
a
Unless otherwise noted, all reactions were conducted with 0.10 mmol of
5a and 0.15 mmol of N-methyl indole 11a in the presence of a promoter
(100 mol%) in solvent (1.0 mL) at refluxing temperature. Isolated yield.
Diastereomeric ratio was determined by comparing the integration value of
b
c
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 5
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
COMMUNICATION
fluorine of CF3 group at C-1 position for each diastereomer in the 19F NMR
spectrum. d With 10 mol% of catalyst. e With 30 mol% of catalyst.
almost negligible effect, and good chemical yields werVeieawcAhriteicvleeOdnflioner
products 10j–l (61–78%). Notably, the reaction was not limited to
DOI: 10.1039/D0OB01582B
simple benzene-type substrate; naphthyl-type product 10m was
obtained in good chemical yield as well (61%, d.r. = 2.2:1).
The favorable effect of Brønsted acids over Lewis acids in the
intermolecular reaction could be well rationalized by considering
the switching of their activation site on substrate 5a. Two
activation pathways could be assumed for the exposure of 5a to
acid catalysts, as shown in Fig. 1: (1) the formation of acyclic
iminium cation species F triggered by the activation of oxygen atom
(undesired activation), and (2) nitrogen atom activation/release
initiated the formation of cyclic oxonium cation
G (desired
activation). In the case of Lewis acid catalysts, undesired oxygen
atom activation occurs preferentially because of their high oxophilic
character. On the other hand, the high Brønsted basicity of
nitrogen atom enables the smooth release of amine moiety H by
Brønsted acids, which leads to the formation of desired oxonium
cation species G.12
Fig. 1 Two possible activation pathways of 5a by acid catalysts.
Gratifyingly, the first [1,4]-hydride shift/cyclization process
proceeded smoothly even when o- and m-xylenes were employed
as the reaction media, and satisfactory chemical yields were
achieved in both cases (86% and 82%, respectively).9 Stimulated by
these results, a one-pot reaction was conducted (Scheme 4).
Heating a mixture of 4a and 10 mol% of Yb(OTf)3 in o-xylene at
100 °C for 20 h followed by additional heating at reflux for 5 h after
the addition of 1.0 equiv. of Tf2NH and 1.5 equiv. of N-methyl indole
11a resulted in the smooth formation of desired adduct 10a in 90%
chemical yield with 1.9:1 diastereoselectivity. An almost identical
result was observed when m-xylene was employed as the reaction
solvent (92%, d.r. = 2.0:1)
Fig. 2 Substrate scope.
In summary, we have achieved an expedient synthesis of 3-
indolyl-1-trifluoromethyl-isobenzofurans via an internal redox
reaction/intermolecular nucleophilic addition reaction
sequence. The notable features of this reaction are as follows:
(1) involvement of the quite rare [1,4]-hydride shift process;
(2) first realization of a one-pot sequential reaction consisting
of internal redox reaction and intermolecular nucleophilic
addition reaction; and (3) construction of indole skeleton
attached 1-trifluoromethyl isobenzofurans, the effective
synthetic methods of which have been quite limited. Both the
hybrid use of Lewis acid and Brønsted acid catalysts, and the
Scheme 4 One-pot reaction.
employment of trifluoromethyl ketone
4
with N,N-
After identifying the optimal reaction conditions for the one-pot
reaction, the substrate scope was examined, as illustrated in Figure
2. Indole derivatives 11b and 11c, namely, N-Et and N-Bn indole,
respectively, indole itself 11d, and 5-substituted indoles 11e
dibenzylaminomethyl group at ortho position were the key to
achieving the reaction, and various types of products were
obtained in moderate to good chemical yields. The synthesis
(methyl) and 11f (bromo) could be employed in this reaction, and of complex molecules based on the internal redox reaction
corresponding adducts 10b–f were obtained in moderate to good
chemical yields (68–81%, d.r. = ca. 2.0:1). Next, the substituent
effect on the aromatic ring was examined with N-methyl indole 11a
as the reaction partner. Substrates 4g–i having not only electron-
donating groups, such as methyl and methoxy, but also an electron-
withdrawing group (fluoro) at 5-position afforded various indole-
attached isobenzofurans 10g–i in moderate to good chemical yields
(53–85%, d.r. = ca. 2.0:1). The position of the substituent had an
involved sequential system is under way in our laboratory.
Conflicts of interest
There are no conflicts of interest to declare.
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 5
COMMUNICATION
Journal Name
L.-F. Li, M.-Y. Xiao, J.-M. Yang, Q. Liu, J. Xiao, J. Org. Chem.
Notes and references
2019, 84, 13935; (w) L. Zhou, X.-D. An, S. YangV,ieXw.-AJr.ticLlie,OCn.l-inLe.
DOI: 10.1039/D0OB01582B
1
For recent reviews on internal redox process, see: (a) M.
Tobisu, N. Chatani, Angew. Chem. Int. Ed. 2006, 45, 1683; (b)
M. Wang, ChemCatChem 2013, 5, 1291; (c) B. Peng, N.
Maulide, Chem, Eur. J. 2013, 19, 13274; (d) L. Wang, J. Xiao,
Adv. Synth. Catal. 2014, 356, 1137; (e) M. C. Haibach, D.
Seidel, Angew. Chem. Int. Ed. 2014, 53, 5010; (f) S. J. Kwon,
D. Y. Kim, Chem. Rec. 2016, 16, 1191; (g) M. Xiao, S. Zhu, Y.
Shen, L. Wang, J. Xiao, Chin. J. Org. Chem. 2018, 38, 328.
For the internal redox reaction developed by our group, see:
(a) K. Mori, Y. Ohshima, K. Ehara, T. Akiyama, Chem. Lett.
2009, 38, 524; (b) K. Mori, T. Kawasaki, S. Sueoka, T.
Akiyama, Org. Lett. 2010, 12, 1732; (c) K. Mori, S. Sueoka, T.
Akiyama, J. Am. Chem. Soc. 2011, 133, 2424; (d) K. Mori, S.
Sueoka, T. Akiyama, Chem. Lett. 2011, 40, 1386; (e) K. Mori,
K. Ehara, K. Kurihara, T. Akiyama, J. Am. Chem. Soc. 2011,
133, 6166; (f) K. Mori, T. Kawasaki, T. Akiyama, Org. Lett.
2012, 14, 1436; (g) K. Mori, K. Kurihara, T. Akiyama, Chem.
Commun. 2014, 50, 3729; (h) K. Mori, N. Umehara, T.
Akiyama, Adv. Synth. Catal. 2015, 357, 901; (i) T. Yoshida, K.
Mori, Chem. Commun. 2017, 53, 4319; (j) M. Machida, K.
Mori, Chem. Lett. 2018, 47, 868; (k) K. Yokoo, K. Mori, Chem.
Commun. 2018, 54, 6927; (l) N. Hisano, Y. Kamei, Y. Kansaku,
M. Yamanaka, K. Mori, Org. Lett. 2018, 20, 4223; (m) T.
Yoshida, K. Mori, K. Chem. Commun. 2018, 54, 12686; (n) R.
Tamura, E. Kitamura, R. Tsutsumi, M. Yamanaka, T. Akiyama,
K. Mori, Org. Lett. 2019, 21, 2383; (o) Y. Otawa, K. Mori,
Chem. Commun. 2020, 55, 13856; (p) K. Yokoo, K. Mori, Org.
Lett. 2020, 22, 244; (q) K. Yokoo, D. Sakai, K. Mori, Org. Lett.
2020, 22, 5801.
Shao, Q. Liu, J. Xiao, Org. Lett. 2020, 22, 776; (x) Y.-B. Shen,
L.-X. Wang, Y.-M. Sun, F.-Y. Dong, L. Yu, J. Xiao, J. Org. Chem.
2020, 85, 1915; (y) K. Duan, X.-D. An, L.-F. Li, L.-L. Sun, B. Qiu,
X.-J. Li, C.-L. Shao, Q. Liu, J. Xiao, Org. Lett. 2020, 22, 2537; (z)
K. Duan, H. Shi, L.-X. Wang, ,S.-S. Li, L. Xu, J. Xiao, Org. Chem.
Front. 2020, DOI: 10.1039/D0QO00658K
5
For examples of the enantioselective internal redox
reactions, see: (a) S. Murarka, I. Deb, C. Zhang, D. Seidel, J.
Am. Chem. Soc. 2009, 131, 13226; (b) Y. K. Kang, S. M. Kim,
D. Y. Kim, J. Am. Chem. Soc. 2010, 132, 11847; (c) W. Cao, X.
Liu, W. Wang, L. Lin, X. Feng, Org. Lett. 2011, 13, 600; (d) G.
Zhou, F. Liu, J. Zhang, Chem. Eur. J. 2011, 17, 3101; (e) Y.-P.
He, Y.-L. Du, S.-W. Luo, L. Z. Gong, Tetrahedron Lett. 2011,
52, 7064; (f) L. Chen, L. Zhang, Z. Lv, J.-P. Cheng, S. Luo,
Chem. Eur. J. 2012, 18, 8891; (g) Z.-W. Jiao, S.-Y. Zhang, C.
He, Y.-Q. Tu, S.-H. Wang, F.-M. Zhang, Y.-Q. Zhang, H. Li,
Angew. Chem. Int. Ed. 2012, 51, 8811; (h) Y. K. Kang, D. Y.
Kim, Adv. Synth. Catal. 2013, 355, 3131; (i) Y. K. Kang, D. Y.
Kim, Chem. Commun. 2014, 50, 222; (j) C. W. Suh, D. Y. Kim,
Org. Lett. 2014, 16, 5374; (k) W. Cao, X. Liu, J. Guo, L. Lin, X.
Feng, Chem. Eur. J. 2015, 21, 1632. See also, refs 2c and 3c.
2
6
For
selected
examples
of
the
hydride-
transfer/intramolecular Friedel-Crafts reaction sequence,
see: (a) G. Zhou, J. Zhang, Chem. Commun. 2010, 46, 6953;
(b) M. C. Haibach, I. Deb, C. Kanta De, D. Seidel, J. Am. Chem.
Soc. 2011, 133, 2100; (c) S. Liu, J. Qu, B. Wang, Chem.
Commun. 2018, 54, 7928; (d) S.-S. Li, L. Zhou, L. Wang, H.
Zhao, L. Yu, J. Xiao, Org. Lett. 2018, 20, 269; (e) S. Wang, Y.-B.
Shen, L.-F. Li, B. Qiu, L. Yu, Q. Liu, J. Xiao, Org. Lett. 2019, 21,
8904.
3
4
For the double C(sp3)–H bond functionalization by sequential
utilization of the internal redox reaction developed by our
group, see: (a) K. Mori, K. Kurihara, S. Yabe, M. Yamanaka, T.
Akiyama, J. Am. Chem. Soc. 2014, 136, 3744; (b) K. Mori, N.
Umehara, T. Akiyama, Chem. Sci. 2018, 9, 7327; (c) K. Mori,
R. Isogai, Y. Kamei, M. Yamanaka, T. Akiyama, J. Am. Chem.
Soc. 2018, 140, 6203; (d) M. Kataoka, Y. Otawa, N. Ido, K.
Mori, Org. Lett. 2019, 21, 9334.
7
8
Unpublished results.
For examples of [1,4]-hydride shift mediated C–H bond
functionalizations, see: (a) Yang, S.; Li, Z.; Jian, X.; He, C.
Angew. Chem. Int. Ed. 2009, 48, 3999. (b) Alajarin, M.;
Martin-Luna, M.; Vidal, A. Adv. Synth. Catal. 2011, 353, 557.
See also, refs 2g and 3b.
9
Detailed examinations of the reaction conditions and
substrates were described in supporting information.
For selected recent examples of the internal redox reactions,
see: (a) S. J. Pastine, K. M. McQuaid, D. Sames, J. Am. Chem.
Soc. 2005, 127, 12180; (b) S. J. Pastine, D. Sames, Org. Lett.
2005, 7, 5429; (c) C. Zhang, C. Kanta De, R. Mal, D. Seidel, J.
Am. Chem. Soc. 2008, 130, 416; (d) K. M. McQuaid, D. Sames,
J. Am. Chem. Soc. 2009, 131, 402; (e) K. M. McQuaid, J. Z.
Long, D. Sames, Org. Lett. 2009, 11, 2972; (f) S. Yang, Z. Li, X.
Jian, C. He, Angew. Chem. Int. Ed. 2009, 48, 3999; (g) P. A.
Vadola, D. Sames, J. Am. Chem. Soc. 2009, 131, 16525; (h) I.
D. Jurberg, B. Peng, E. Wöstefeld, M. Wasserloos, N.
Maulide, Angew. Chem. Int. Ed. 2012, 51, 1950; (i) D.-F.
Chen, Z.-Y. Han, Y.-P. He, J. Yu, L.-Z. Gong, Angew. Chem. Int.
Ed. 2012, 51, 12307; (j) Y.-Z. Li, M.-L.; Zhao, W.-F. Chang, X.
Wen, H. Sun, Q.-L. Xu, J. Org. Chem. 2015, 80, 9620; (k) K.
Eamakumar, T. Maji, J. J. Partridge, J. A. Tunge, Org. Lett.
2017, 19, 4014; (l) S.-S. Li, L. Zhou, L. Wang, H. Zhao, L. Yu, J.
Xiao, Org. Lett. 2018, 20, 138; (m) S.-S. Li, X. Jv, C.-L. Shao, Q.
Liu, J. Xiao, Chem. Sci. 2018, 9, 8253; (n) S. Wang, X. D. An, S.
S. Li, X. Liu, Q. Liu, J. Xiao, Chem. Commun. 2018, 54, 13833;
(o) S.-S. Li, S. Zhu, C. Chen, K. Duan, Q. Liu, J. Xiao, Org. Lett.
2019, 21, 1058; (p) X. Lv, F. Hu, K. Duan, S.-S. Li, Q. Liu, J.
Xiao, J. Org. Chem. 2019, 84, 1833; (q) S. Zhao, X. Wang, P.
Wang, G. Wang, W. Xhao, X. Tang, M. Guo, Org. Lett. 2019,
21, 3990; (r) S. Zhu, C. Chen, K. Duan, Y.-M. Sun, S.-S. Li, Q.
Liu, J. Xiao, J. Org. Chem. 2019, 84, 8440; (s) A. Paul, D.
Seidel, J. Am. Chem. Soc. 2019, 141, 8788; (t) L. Zhou, Y.-B.
Shen, X.-D. An, X.-J. Li, S.-S. Li, Q. Liu, J. Xiao, Org. Lett. 2019,
21, 8543; (u) X.-D. An, K. Duan, X.-J. Li, J.-M. Yang, Y.-N. Lu,
Q. Liu, J. Xiao, J. Org. Chem. 2019, 84, 11839; (v) Y.-B. Shen,
10 Interestingly, not only the CF3-ketone 4a, but also
intramolecular cyclization adduct 4a’ were observed in the
NMR spectrum. This tendency was also observed in the
substrates 4g–m except for 4j.
11 D. P. Becker, H. Li, D. L. Flynn, Synth. Commun. 1996, 26,
3127.
12 Some trials to obtain the evidence of this assumption failed.
1
For example, only the broad peaks were observed in the H
NMR spectra of the mixture of 5a and acid catalysts such as
Tf2NH and BF3•OEt2 (5a:acids = 1:1).
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/D0OB01582B
Expeditious synthesis of 3-indolyl-1-trifluoromethyl-isobenzofurans via [1,4]-hydride
shift/cyclization/intermolecular nucleophilic addition reaction sequence.
Lewis acid
promoted reaction
N
O
N
H
H
R3
CF3
CF3
R2
CF3
Yb(OTf)3 (10 mol%)
Tf2NH (1.0 equiv.)
O
O
H
[1,4]-H shift
intermolecular
nucleophilic addtion
R1
R1
R1
N
Ph
Ph
Ph
N
Ph
R3
R2
up to 92%, d.r. = 2.0:1
Brønsted acid
promoted reaction