A comparative study of thallium(iii) and iodine(iii)-mediated ring contraction reactions for the synthesis of indane

Article abstract of DOI:10.1039/d0nj04700g

Reported herein is a comparative study of the synthesis of indaneviaring contraction reaction, mediated by iodine(iii) and thallium(iii). A series of protected 1,2-dihydronaphthalenes were synthesized and subjected to hydroxy(tosyloxy)iodobenzene (HTIB) and thallium(iii) nitrate trihydrate (TTN) in trimethyl orthoformate (TMOF) to compare the percent yields provided by both oxidizing agents. The yields of the ring contracted products (indanes) were in the range of 61-88% for reactions performed with TTN·3H₂O in TMOF. However, the yields were found to be significantly lower (e.g., 18-34%) when using HTIB in TMOF with some addition products. This study provides an important development related to the efficacy of the two oxidizing agents for ring contraction reaction.

Full text of DOI:10.1039/d0nj04700g

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A Comparative Study of Thallium(III) and Iodine(III)-Mediated Ring Contraction
Reactions for the Synthesis of Indane
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Ajmir Khan,*a,b Luiz F. Silva Jr.,a† Muhammad Rabnawaz*b
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aDepartment of Fundamental Chemistry, Institute of Chemistry, University of São Paulo, Av.
Prof. Lineu Prestes, 748, São Paulo, SP CEP 05508-000, Brazil
bSchool of Packaging, Michigan State University, 448 Wilson Road, East Lansing, MI 48824-
1223, USA.
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*Corresponding authors:
Muhammad Rabnawaz rabnawaz@msu.edu
Ajmir Khan khanajmi@msu.edu
Reported herein, is a comparative study for the synthesis of indane via ring contraction
reaction, mediated by iodine(III) and thallium(III). A series of protected 1,2-dihydronaphthalenes
were synthesized, and subjected to hydroxy(tosyloxy)iodobenzene (HTIB) and thallium(III) nitrate
trihydrate (TTN) in trimethyl orthoformate (TMOF) to compare the percent yields provided by both
oxidizing agents. The yields of the ring contracted products (indanes) were in the range of 61-
88% for reactions performed with TTN.3H2O in TMOF. However, these yields were recorded
significantly lower (e.g., 18-34%) while used HTIB in TMOF with some addition products. This
study provides an important development related to the efficacy of two oxidizing agents for ring
contraction reaction.
Keywords: ring-contraction, iodine(III), thallium(III), 1,2 dihydronaphthalenes, indanes
Introduction.
Indanes, also known as benzocyclopentanes, and its derivatives, display important
biological activities, including anti-allergic, anti-tumor, anti-convulsant, anti-hypercholesterolemic,
herbicidal, fungicidal and antimicrobial activities.1 Indane derivatives also have numerous
applications in the fields of material science and nanoscience.2 Moreover, indane moieties are
important constituents of many natural products3–7 and comprise the backbone of various potential
therapeutic agents.8–10 Scheme 1 summarizes the efficient synthetic approaches, reported by
various authors for the development of indane-based natural products.1 These include but not
limited to intramolecular Friedel-Crafts-type cyclization reactions,11 cycloaddition reactions,12
cyclization involving Michael-type addition reactions,13 cyclization involving Heck-type
reactions,14,15 Prins-type reactions 16 and ring contraction reaction of tetralones via TI(III) or I(III).17

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The oxidative rearrangement of six-membered carbocycles into indanes is a promising, versatile
and efficient strategy.18
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Thallium(III) and iodine(III) are the two effective and practical oxidizing agents. Both
oxidants have some similar but interesting synthetic applications in organic chemistry. For
example, both of these agents are in cyclization of alkenols,19,20 phenolic oxidative coupling,21,22
oxidative rearrangement,23–25 and readily reacts with phenols,26 or nitrogen of the indoles.25,27
However, the scope of commercially available TTN-mediated ring contraction reactions involving
cyclohexane derivatives is relatively well-explored.28–30 In recent years, the conversion of 1,2-
dihydronaphthalene and its derivatives to the corresponding indane products
(benzocyclopentanes) via treatment with thallium salt (TTN) in suitable solvents have been
extensively studied by Dr. Silva, Jr. group.31–33 For example, the total synthesis of phenolic
sesquiterpene (±)-mutisiantol (2) was performed via the rearrangement of the corresponding 1,2-
dihydronaphthalene substrate using thallium(III) in TMOF. The resulting indane was isolated in
94% yield. This reaction was the key step in both the racemic as well as in the asymmetric
synthesis of mutisianthol (2).34,35 Similarly, the chemoselectively total synthesis of an
antimicrobial alkaloid, trans-trikentrin A (4), was accomplished by using TTN.36
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HO
HO
(2)
Me
OH
Cl
(+)-Mutisianthol
OH
(3)
(9)
OH
Cl
(±)-Jungianol
Tripartin
OH
OH
NH
COOH
O
(8)
1
(4)
O
Fomajorin D
-Trikentrine A
trans
NH
NHMe.HCl
O
HO
Rasagiline
(MAO inhibitors)
(5)
(±)-indatraline
(7)
OH
Cl
Cl
(6)
OH
Paucifloral F
HO
OH
Scheme 1. Indane-based natural products and their analogues.

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Apart from the synthetic application, thallium has strong application nature in industry such
as semiconductor production, optical glasses, alloys, photoelectric cells, radioisotopes, etc.37
Despite the importance of thallium, the toxicity of thallium salts for aquatic life has raised interest
for safer alternatives.38,39 In this direction, hypervalent iodine reagents were developed as an
environmentally benign alternative and drawn intense interest from chemists during the last two
decades.40–43
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HTIB (hydroxy-(tosyloxy)iodo]benzene or Koser’s reagent) has been found to be an
efficient tool for promoting ring contraction reaction.44,45 Several articles describe the synthesis of
indanes through HTIB-promoted ring contraction reactions.17,46,47 For instance, (±)-Indatraline (7)
is a potent drug capable of counteracting the effects of cocaine. The diastereoselective total
synthesis of (±)-indatraline (7) using ring contraction reaction with HTIB in MeOH has been
developed as the vital step.10 As the choice of solvent has great importance in these
rearrangement reactions. For example, acetal formation has been observed with the use of
nucleophilic solvents such as TMOF, EtOH, MeOH, or TFE (2,2,2-trifluoroethanol).48
In this study, we are here describing a comparative study for the synthesis of indane via ring
contraction reaction, mediated by iodine(III) and thallium(III). A series of various protected 1,2-
dihydronaphthalenes were subjected to HTIB and TTN in TMOF under similar reaction conation,
to compare the yields. To the best of our knowledge, no prior research has reported to compare
iodine(III) and thallium(III) mediated ring contraction reactions for the same substrate. Moreover,
various protecting group were introduced to the substrates, aim to study the protection group
tolerance for both oxidizing agents. Therefore, this study provides significant development about
the two oxidizing reagents in terms of effectiveness for ring contraction reactions.
Results and discussion.
To study ring contraction reaction for the synthesis of indane skeleton, a series of 1,2-
dihydronaphthalenes bearing various substituents were prepared (see Supporting Information)
followed by their treatment with HTIB and TTN in TMOF to compare the reactivities as well as the
yields of both oxidative agents. These results are summarized in Tables 1 and 2. Compound 14a
was treated with HTIB in TMOF and the resulting acetal product was isolated in 29% yield (Table
1, entry 1). Previously, poor yields in MeOH or TMOF for reactions involving methoxy-substituted
1,2-dihydronaphthaline compounds was reported.48 The low yield of the ring-contracted product
can likely be attributed to the electron-donating effect of the methoxy group, which increases the
reactivity of the cationic intermediate produced by the iodine(III) species, thus causing the
formation of byproducts some.48

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In subsequent reactions, the electron-donating effect was decreased via the introduction
of protective groups such as t-butyldiphenylsilyl meta and para to the migratory carbon of the ring.
Compounds 14b and 14c reacted with HTIB in TMOF forming the corresponding acetals 15b and
15c, in 28% and 34% yields, respectively (Table 1, entries 2 and 3). The reaction of tosyl- and
2,4,6-trimethylbenzoyl-protected alkenes (14d and 14e) with HTIB in TMOF gave four distinctive
products. Tosyl-protected alkene 14d led to the ring contraction product 15d, in 29% yield, the
cis-addition product 16d, in 16% yield, the trans-addition product 17d, in 18% yield, and the
aromatized product 18d, in 3% yield (entry 4). Similarly, alkene 14e led to the ring-contracted
product 15e, in 31% yield, the cis addition product 16e, in 15% yield, the trans addition product
17e, in 17% yield, and the aromatized product 18e, in 4% yield (Table 1, entry 5).
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The dimethoxy 1,2-dihydronaphthalene compound 14f was also treated with HTIB that gave the
corresponding indane in 18% yield with two addition byproducts of (cis- and trans) and an
aromatic product (Table 1, entry 6). The HTIB-mediated oxidation of benzamide 14g was
monitored by TLC analysis, which showed four spots, but only the ring contraction product 15g
and trans-addition product 17g could be isolated in 32% and 19% yields, respectively (Table 1,
entry 7).
Table 1 HTIB-mediated ring contraction reactions in TMOF.
Entr
y
Substrate
Acetal (Indane)
Addition product
Addition product
aromatization
(cis)
(trans)
MeO
OMe
1
2
***
***
***
***
***
MeO
MeO
(29%)
OMe
15a
MeO
14a
14b
Ph
Ph Si
O
Ph
Ph Si
(28%)
15b
O
***
***
MeO
OMe
Ph Ph
Si
Ph Ph
Si
3
4
***
***
O
O
15c (34%)
14c
MeO
OMe
OMe
O
O
S
OMe
OMe
OMe
S
O
O
O
O
O
O
O
14d
18d
(3%)
S
O
S
O
S
O
O
O
O
17d
(18%)
16d
(16%)
(29%)
15d

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OMe
OMe
MeO
O
O
OMe
OMe
OMe
4
5
6
7
8
9
O
O
O
O
O
18e (4%)
14e
O
O
5
6
16e
O
(15%)
17e
(17%)
15e
(31%)
OMe OMe
OMe
OMe
OMe OMe
MeO
OMe
OMe
OMe
OMe
OMe
14f
(25%)
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(21%)
16f OMe
(2%)
17f OMe
18f
OMe
O
(18%)
MeO
OMe
O
15f
OMe
OMe
OMe
O
N
H
14g
N
H
7
***
***
N
H
17g
(19%)
15g
(32%)
*** = Compounds analyzed by TLC but could not characterized due to their low yields.
Reaction conditions: 1.2 equiv HTIB, TMOF, rt, 5 min
Our data clearly supports that HTIB-mediated oxidation of alkenes in TMOF gave the
corresponding acetals as major products but with low yields (28-34%), except for 14f. However,
these yields were considerably improved when iodine(III) was replaced with thallium(III) in TMOF.
For example, the reaction of alkenes 14a-c with TTN in TMOF provided the resulting acetal
products (15a-c) in 88%, 74%, and 79% yields, respectively (Table 2, entries 1-3) in contrast to
the yields when HTIB was employed (29%, 28% and 34% yields, respectively) as depicted in
Table 1, entries 1-3. The reaction of tosyl-protected alkenes 14d with TTN in TMOF produced the
resulting acetal 15d, in 69% yield, with the cis-addition product 16d, in 8% yield, and the trans-
addition product 17d, in 11% yield (Table 2, entry 4). Similarly, 2,4,6-trimethylbenzoyl-protected
alkene 14e gave the ring contraction product 15e in 61% yield with two minor addition products
cis- and trans-products, in 9% and 12% yields, respectively (Table 2, entry 5).
Table 2 TTN-mediated ring contraction reactions in TMOF.
Entry
Substrate
Acetal (Indane)
Addition product
Addition products
(cis)
(trans)
MeO
OMe
1
MeO
MeO
15a
88%)
OMe
14a
MeO
Ph
Ph Si
14b
15b (74%)
O
Ph
Ph Si
O
2
3
***
***
***
***
MeO
OMe
Ph Ph
Ph Ph
Si
Si
O
O
15c
(79%)
14c

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OMe
OMe
MeO
OMe
OMe
OMe
O
S
O
O
S
O
S
O
S
O
O
O
O
O
17d
(18%)
O
16d (16%)
O
15d (69%)
14d
4
5
7
8
9
OMe
OMe
MeO
OMe
O
OMe
OMe
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O
O
O
O
O
14e
O
O
16e
17e
(15%)
(17%)
15e
(61%)
OMe
MeO
OMe
OMe
6
7
***
***
***
14f
OMe
O
15f OMe
(72%)
MeO
OMe
N
H
O
14g
***
N
H
15g
(68%)
*** = Compounds analyzed by TLC but could not characterized due to their low yields.
Reaction conditions: 1.2 equiv TTN.3H2O, TMOF, rt, 5 min
Alkenes 14f and 14g were subjected to the TTN-mediated rearrangement reaction and
the anticipated ring contraction products 15f and 15g were isolated in 72% and 68% yields,
respectively (Table 2, entries 6 and 7). Comparing these yields with those reported in Table 1 for
the HTIB-mediated reactions, it is clear that TTN provides much better yields than HTIB.
Additionally, a comparison of the yields reported in tables 1 and 2 demonstrates that fewer
addition or aromatization byproducts were observed when TTN was employed as the oxidizing
agent. In conclusion, the reactions of the 1,2-dihydronaphthalenes with TTN proceeded in an
efficient manner and provided good yields of the ring-contracted acetals.
The mechanism for the formation of indane via ring contraction reaction promoted by
iodine(III) is described below in Scheme 2. This mechanism has also been recently investigated
by the DFT (Density Functional Theory) calculation methods of computational chemistry.49 The
first step of the mechanism is the ionization of iodine(III), which leads to the formation of PhIOH+,
followed by its electrophilic addition to the double bond of alkene 13 to form the benzylic
carbocation 14. In the nucleophilic addition of the solvent, the theoretical approach of Solvation
Model Density (SMD) continuum solvation model showed that the addition occurs via a cluster of
solvent molecules. Moreover, DFT calculation also showed that the trans-addition of MeOH
cluster to carbocation 14 occurs with less potential energy and less free energy as compared to
their cis addition. The final step of the mechanism is the migration of the aryl group where the
protonation of the hydroxyl group by the MeOH cluster 16, followed by the elimination of H2O, to

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afford 17. The C-I bond becomes weaker after the removal of H2O and the required antiperiplanar
18 arrangement is formed. In the subsequent step, the formation of C-C bond followed by the loss
of iodobenzene, ring contraction leads to a five-membered ring 20.
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Nucleophilic addition of the solvent
Electrophilic addition of HTIB
and deprotonation
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Trans addition of the solvent cluster
Me
O
H
H
carbocation
to the
have less potential
and free energy compared to cis addition.
H
H
H
H
13
H
H
Me O
O Me
Ph
I
H
H
H
H
H
OMe
H
(MeOH)3
MeOH
H
H
OH
14
H
OMe
H
Ph
I
H
H
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H
Ph
I
H
(MeOH)3
MeOH
OH
H
TsO
OH
H
H
TsO I OH
15
Ph
I
3MeOH
H2O
OH
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H
H
H
OMe
H
H
H
H
H
H
H
H
H
H
-PhI
anti
-periplanarity
20
OMe
19
18
17
H
MeOH
MeO
H
I
H
OMe
H
I
OMe
Ph
Ph
Migration of the aryl group
Scheme 2 Ring contraction mechanism, mediated by iodine(III).
Scheme 3 summarizing the proposed mechanistic approaches, for the for the formation of
trans- and cis-addition products.

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Mechanism of the trans addition
H
Me
OMe
H
O
OMe
H
MeOH
H
H
17
22
PhI
H
21
OMe
I
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Ph
Mechanism of the cis addition
H
OMe
H
OMe
OMe
MeOH
H
H
H
PhI
17
23
H
I
Ph
Scheme 3 HTIB-mediated mechanism for the formation of trans- and cis-addition products.
In the proposed mechanism,28,31,50 the formation of the thallonium ion 24 is the first step.
After the ring-opening occurs in a Markovnikov sense, the thallonium ion leads to the
corresponding trans oxythallated adduct 25. This intermediate subsequently undergoes
rearrangement, giving the resulting acetal compound 20, after the addition of MeOH to the
oxonium 26, and subsequent deprotonation (Scheme 4A).
In the case of cis and trans addition products, the thallonium ion 24 allowed ring-opening,
which led to trans oxythallated adduct 25, and the oxonium ion 27 is formed via the reductive
elimination of thallium(III). The addition of a second solvent molecule leads to the trans-1,2-
dimethoxylated isomer 22, followed by deprotonation step (Scheme 4C). The formation of the cis
isomer 23 would proceed directly from 25 after the elimination of the thallium(III) by the MeOH,
followed by deprotonation step (Scheme 4B).

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O2NO
ONO2
ONO2
Tl
OMe
Tl
TTN
ONO2
MeOH
- H+
-
- NO3
13
25
24
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A
Mechanism of the Ring Contraction
MeO
OMe
OMe
MeOH
- H+
- TlNO3
-
26
20
- NO3
B
Mechanism of the cis addition
ONO2
Tl
OMe
OMe
OMe
ONO2 MeOH
MeOH
- H+
24
- TlNO3
-
23
cis
25
- NO3
- TlNO3
Mechanism of the trans addition
C
-
- NO3
OMe
OMe
OMe
MeOH
- H+
trans
22
27
Scheme 4. Proposed mechanism for A) TTN-mediated ring contraction reaction; B) TTN-
mediated cis dimethoxylated addition reaction; and C) TTN-mediated reactions for the trans
dimethoxylated addition product.
Conclusion.
A series of protected 1,2-dihydronaphthalenes were subjected to HTIB and TTN in TMOF.
Comparing these values of TTN-mediated reaction with those reported with HTIB-mediated, it is
clear that the thallium(III) salt is much better than iodine(III) oxidizing agent for indane synthesis.
Similarly, the TTN-mediated reactions are less prone to form addition byproducts compared to
the HTIB-mediated reactions of 1,2-dihydronaphthalenes. Moreover, the tolerance of various
protecting groups were also investigated while used thallium(III) and iodine(III). These findings
will positively impact research towards indane synthesis for biomedical research.
Experimental.
HTIB-mediated oxidation of cyclic alkenes in TMOF; General procedure

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To the stirred solution of alkene 14b-14g in TMOF (4 mL) was added 1.2 equiv HTIB at rt.
After 5 min the reaction mixture was quenched by adding saturated solution of NaHCO3 (10 mL),
followed by extraction with DCM (3 x 10 mL), dried over anhydrous MgSO4, filtrated and
evaporated the solvents under vacume pressure. The crude residue was purified by flash column
chromatography. (see characterization data for all novel compounds in ESI).
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TTN.3H2O-mediated oxidation of cyclic alkenes in TMOF; general reaction.
TTN.3H2O (1.2 equiv) was added to the solution of alkenes 14a-g in TMOF (4 mL) at rt
and stirred for 5 min. The resulting precipitation was filtrated via silica gel pad (200-400 Mesh, ca,
10 cm), using CH2Cl2 as eluent. The filtrate was collected in conical flask was latter washed with
H2O (2 x 10 mL) and brain (10 mL) followed by drying over MgSO4. Rota-evaporator was used to
remove the solvent. The obtained crude residues were purified by flash column chromatography.
Their Yields are given in the table 2, while physical states, IR (film), 1H NMR and 13C NMR data
are given above.
Acknowledgment
The authors thank CAPES, FAPESP, CNPq and Michigan State University MI, USA for financial
support.
Conflicts of interest
There are no conflicts to declare
Author Contributions
A.K. Conceived the original synthetic proposal, carried out all the experimental work; M.R. and
A.K. wrote the manuscript; and L.F.S. conceived the main idea.
Notes
Luiz F. Silva Jr.† In memoriam.
Supporting Information
Analytical data (1H NMR, 13C NMR) for all new compounds. see SI DOI:
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Table of contents entry
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Ring contraction reactions were carried out using HTIB and TTN to compare yields as will as the
protection group tolerance
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